Substituted chromenes as kinase modulators

ABSTRACT

The present invention provides PI3K protein kinase modulators of formula (I): 
                         
wherein R, R 1 , R 2 , L 1 , Cy 1 , Cy 2  and n are as described herein, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

This application is a continuation of U.S. patent application Ser. No.13/292,746, filed on Nov. 9, 2011, which is continuation of U.S. patentapplication Ser. No. 12/938,609, filed on Nov. 3,2010, which claims thebenefit of Indian Provisional Patent Application Nos. 2690/CHE/2009dated 5 Nov. 2009, and 1429/CHE/2010 dated 24 May 2010, and U.S.Provisional Patent Application No. 61/364,661 dated 15 Jul. 2010, eachof which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention provides PI3K protein kinase modulators, methodsof preparing them, pharmaceutical compositions containing them andmethods of treatment, prevention and/or amelioration of kinase mediateddiseases or disorders with them.

BACKGROUND OF THE INVENTION

In the recent past immense research has been dedicated to the discoveryand understanding of the structure and functions of enzymes andbio-molecules associated with various diseases. One such important classof enzymes that has been the subject of extensive research is ProteinKinase.

In general, protein kinases represent a set of structurally relatedphosphoryl transferases having conserved structures and catalyticfunctions. These enzymes modify proteins by chemically adding phosphategroups (phosphorylation). Phosphorylation involves the removal of aphosphate group from ATP and covalently attaching it to amino acids thathave a free hydroxyl group such as serine, threonine or tyrosine.Phosphorylation usually results in a functional change of the targetprotein (substrate) by altering enzyme activity, cellular localizationor association with other proteins. Up to 30% of all proteins may bemodified by kinase activity.

This class of proteins are classified into subsets depending upon thesubstrate they act upon such as tyrosine kinase, serine/theroninekinase, histidine kinase and the like. These proteins can also beclassified based on their localization into receptor tyrosine kinases(RTKs) or non-receptor tyrosine kinases.

Receptor tyrosine kinases (RTKs) have an extracellular portion, atransmembrane domain, and an intracellular portion, while non-receptortyrosine kinases are entirely intracellular. Receptor tyrosine kinasemediated signal transduction is typically initiated by an extracellularinteraction with a specific growth factor (ligand), followed by receptordimerization, stimulation of the intrinsic protein tyrosine kinaseactivity, and phosphorylation of amino acid residues. The ensuingconformational change leads to the formation of complexes with aspectrum of cytoplasmic signalling molecules and facilitates a myriad ofresponses such as cell division, differentiation, metabolic effects, andchanges in the extracellular microenvironment.

Protein kinases are known to control a wide variety of biologicalprocesses such as cell growth, survival and differentiation, organformation and morphogenesis, neovascularisation, tissue repair andregeneration. In addition to their functions in normal tissues/organs,many protein kinases also play specialized roles in a host of humandiseases including cancer. A subset of protein kinases (also referred toas oncogenic protein kinases), when dysregulated, can cause tumorformation and growth and contribute to tumor maintenance and progression(Blume-Jensen P et al, Nature 2001, 411(6835):355-365). Thus far,oncogenic protein kinases represent one of the largest and mostattractive groups of protein targets for therapeutic intervention anddrug development.

Both receptor and non-receptor protein kinases have been found to beattractive targets for small molecule drug discovery due to their impacton cell physiology and signalling. Dysregulation of protein kinaseactivity thus leads to altered cellular responses including uncontrolledcell growth associated with cancer. In addition to oncologicalindications, altered kinase signalling is implicated in numerous otherpathological diseases. These include, but are not limited toimmunological disorders, cardiovascular diseases, inflammatory diseases,and degenerative diseases.

Modulation (particularly inhibition) of cell proliferation andangiogenesis, the two key cellular processes needed for tumor growth andsurvival is an attractive goal for development of small-molecule drugs(Matter A. Drug Disc Technol 2001, 6, 1005-1024). Anti-angiogenictherapy represents a potentially important approach for the treatment ofsolid tumors and other diseases associated with dysregulatedvascularisation including ischemic coronary artery disease, diabeticretinopathy, psoriasis and rheumatoid arthritis. Similarly, cellantiproliferative agents are desirable to slow or inhibit the growth oftumors.

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of anumber of phospholipids found in cell membranes. In recent years it hasbecome clear that PI plays an important role in intracellular signaltransduction. Cell signaling via 3′-phosphorylated phosphoinositides hasbeen implicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity(Rameh et al (1999) J. Biol Chem, 274:8347-8350). The enzyme responsiblefor generating these phosphorylated signaling products,phosphatidylinositol 3-kinase (also referred to as PI 3-kinase or PI3K),was originally identified as an activity associated with viraloncoproteins and growth factor receptor tyrosine kinases thatphosphorylate phosphatidylinositol (PI) and its phosphorylatedderivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al(1992) Trends Cell Biol 2:358-60).

The phosphoinositide 3-kinases (PI3Ks) are a family of enzymes thatregulate diverse biological functions in every cell type by generatingphosphoinositide second-messenger molecules. As the activity of thesephosphoinositide second messengers is determined by theirphosphorylation state, the kinases and phosphatises that act to modifythese lipids are central to the correct execution of intracellularsignaling events. Phosphoinositide 3-kinases (PI3K) phosphorylate lipidsat the 3-hydroxyl residue of an inositol ring (Whitman et al (1988)Nature, 332:664) to generate phosphorylated phospholipids (PIP3s) whichact as second messengers recruiting kinases with lipid binding domains(including plekstrin homology (PH) regions), such as Akt andphosphoinositide-dependent kinase-1 (PDK1). Binding of Akt to membranePIP3s causes the translocation of Akt to the plasma membrane, bringingAkt into contact with PDK1, which is responsible for activating Akt. Thetumor-suppressor phosphatase, PTEN, dephosphorylates PIPS and thereforeacts as a negative regulator of Akt activation. The PI3-kinases Akt andPDK1 are important in the regulation of many cellular processesincluding cell cycle regulation, proliferation, survival, apoptosis andmotility and are significant components of the molecular mechanisms ofdiseases such as cancer, diabetes and immune inflammation (Vivanco et al(2002) Nature Rev. Cancer 2:489; Phillips et al (1998) Cancer 83:41).

The PI3K family is constituted by four different classes: classes I, IIand III are lipid kinases while members of class IV are Ser/Thr proteinkinases.

The members of the class I family of PI3Ks are dimers of a regulatoryand a catalytic subunit. The class I family consists of four isoforms,determined by the catalytic subunits α, β, γ and δ (see Engelman J A,Nat Rev Genet. 2006; 7:606-19; Carnero A, Curr Cancer Drug Targets 2008;8:187-98; Vanhaesebroeck B, Trends Biochem Sci 2005; 30:194-204). ClassI can be subdivided into two subclasses: Ia, formed by the combinationof p110α β and δ and a regulatory subunit (p85, p55 or p50) and Ib,formed by p110γ and p101 regulatory subunits. The regulatory subunit p85contains Src homology 2 domains, which bind to phosphotyrosines andbring the attached catalytic subunit p110 into the complexes located inthe membrane around the receptor. The activation of PI3K is induced bygrowth factors and insulin targeting the catalytic subunit to themembrane where it is in close proximity with its substrates, mainlyPIP2. Alternatively, GTP-bound Ras can bind and activate p110 subunitsin a p85-independent manner. Class I phosphoinositide 3-kinases (PI3Ks)are lipid kinases that phosphorylate phosphatidyl-inositide lipids (PI)at the D3 position of the inositol ring producing lipid secondmessengers (PIPs). The products of PI3K activity, mainly PI(3,4,5)-P3(PIP3), are present in very low level in quiescent cells but are rapidlyproduced during cell stimulation and are involved in the regulation ofseveral biological responses including mitogenesis, apoptosis, vesiculartrafficking and cytoskeleton rearrangement. The result of rising PIP3levels is the activation of 3-phosphoinositide-dependent proteinkinase-1 and its substrate AKT, which triggers most of the biologicalactivities of the pathway. Phosphatase and tensin homolog in chromosome10 (PTEN) is a lipidic phosphatase which constitutes the main negativeregulator of the route by dephosphorylating PIP3 to PI(4,5)-P2 (PIP2).Class II displays the ability to phosphorylate PI and PI-4 phosphate invitro. Class III, composed by Vps34 only member, phosphorylates PI atposition 3 generating PI 3-phosphate. Vps34 has been implicated in Golgitrafficking of proteins, autophagy and activation of mammalian target ofrapamycin (mTOR) by amino acids (see Backer J M. Biochem J 2008;410:1-17) these classes are generally resistant to class I PI3Kinhibitors. Class IV, however, is important because it constitutes themajor cross-activity proteins for class I inhibitors. This classincludes enzymes involved in signal transduction and DNA damage responsesuch as mTOR, DNA-dependent protein kinase (DNA-PK) or ATM. This fourthclass of PI3K-related enzymes contains a catalytic core similar to thePI3K, which can account for the cross-inhibition by class I ‘selective’compounds. However, small differences, especially in the hinge region,and the solving of the PI3K-related structures might lead to the finetuning of different paralog selective PI3K-members. (see Expert Opin.Investig. Drugs (2009) 18(9): 1265-1277)

There is now considerable evidence indicating that Class Ia PI3K enzymescontribute to tumourigenesis in a wide variety of human cancers, eitherdirectly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer,2002, 2, 489-501). For example, the pi 10a subunit is amplified in sometumours such as those of the ovary (Shayesteh et al, Nature Genetics.1999, 21: 99-102) and cervix (Ma et al, Oncogene, 2000, 19: 2739-2744).More recently, activating mutations within the catalytic site of pi 10ahave been associated with various other tumours such as those of thecolorectal region and of the breast and lung (Samuels et al, Science,2004, 304, 554). Tumour-related mutations in p85α have also beenidentified in cancers such as those of the ovary and colon (Philp etal., Cancer Research, 2001, 61, 7426-7429). In addition to directeffects, it is believed that activation of Class Ia PI3K contributes totumourigenic events that occur upstream in signalling pathways, forexample by way of ligand-dependent or ligand-independent activation ofreceptor tyrosine kinases, GPCR systems or integrins (Vara et al, CancerTreatment Reviews, 2004, 30, 193-204). Examples of such upstreamsignalling pathways include over-expression of the receptor tyrosinekinase Erb2 in a variety of tumours leading to activation ofPI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114)and over-expression of the oncogene Ras (Kauffmann-Zeh et al., Nature,1997, 385, 544-548). In addition, Class Ia PBKs may contributeindirectly to tumourigenesis caused by various downstream signallingevents. For example, loss of the effect of the PTEN tumour-suppressorphosphatase that catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2is associated with a very broad range of tumours via deregulation ofPI3K-mediated production of PI(3,4,5)P3 (Simpson and Parsons, Exp. CellRes. 2001, 264, 29-41). Furthermore, augmentation of the effects ofother PI3K-mediated signalling events is believed to contribute to avariety of cancers, for example by activation of Akt (Nicholson andAnderson, Cellular Signalling, 2002, H, 381-395).

In addition to a role in mediating proliferative and survival signallingin tumour cells, there is also good evidence that Class Ia PI3K enzymeswill also contribute to tumourigenesis via its function intumour-associated stromal cells. For example, PI3K signalling is knownto play an important role in mediating angiogenic events in endothelialcells in response to pro-angiogenic factors such as VEGF (Abid et al.,Arterioscler. Thromb. Vase. Biol., 2004, 24, 294-300). As Class I PI3Kenzymes are also involved in motility and migration (Sawyer, ExpertOpinion Investig. Drugs, 2004, JJ., 1-19), PI3K inhibitors shouldprovide therapeutic benefit via inhibition of tumour cell invasion andmetastasis.

In addition, Class I PI3K enzymes play an important role in theregulation of immune cells with PI3K activity contributing topro-tumourigenic effects of inflammatory cells (Coussens and Werb,Nature, 2002, 420, 860-867). These findings suggest that pharmacologicalinhibitors of Class I PI3K enzymes should be of therapeutic value fortreatment of the various forms of the disease of cancer comprising solidtumours such as carcinomas and sarcomas and the leukaemias and lymphoidmalignancies. In particular, inhibitors of Class I PI3K enzymes shouldbe of therapeutic value for treatment of, for example, cancer of thebreast, colorectum, lung (including small cell lung cancer, non-smallcell lung cancer and bronchioalveolar cancer) and prostate, and ofcancer of the bile duct, bone, bladder, head and neck, kidney, liver,gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes,thyroid, uterus, cervix and vulva, and of leukaemias (including ALL andCML), multiple myeloma and lymphomas.

A recent review by Romina Marone et. al., describes the activation ofthe PI3K signalling cascade having a positive effect on cell growth,survival and proliferation. Constitutive up-regulation of PI3K signalingcan have a deleterious effect on cells leading to uncontrolledproliferation, enhanced migration and adhesion-independent growth. Theseevents favor not only the formation of malignant tumors, but also thedevelopment of inflammatory and autoimmune disease indicating the roleof PI3K in various diseases including chronic inflammation & allergy,Cardiovascular diseases, cancer and metabolic disorders. (see Biochimicaet Biophysica Acta 1784 (2008) 159-185).

Several components of the PI3-kinase/Akt/PTEN pathway are implicated inoncogenesis. In addition to growth factor receptor tyrosine kinases,integrin-dependent cell adhesion and G-protein coupled receptorsactivate PI3-kinase both directly and indirectly through adaptormolecules. Functional loss of PTEN (the most commonly mutatedtumor-suppressor gene in cancer after p53), oncogene mutations in PI3kinase (Samuels et al (2004) Science 304:554), amplification ofPI3-kinase and overexpression of Akt have been established in manymalignancies. In addition, persistent signaling through thePI3-kinase/Akt pathway by stimulation of the insulin-like growth factorreceptor is a mechanism of resistance to epidermal growth factorreceptor inhibitors such as AG1478 and trastuzumab. Oncogenic mutationsof p110alpha have been found at a significant frequency in colon,breast, brain, liver, ovarian, gastric, lung, and head and neck solidtumors. PTEN abnormalities are found in glioblastoma, melanoma,prostate, endometrial, ovarian, breast, lung, head and neck,hepatocellular, and thyroid cancers.

The levels of phosphatidylinositol-3,4,5-triphosphate (PIPS), theprimary product of PI3-kinase activation, increase upon treatment ofcells with a variety of agonists. PI3-kinase activation, therefore, isbelieved to be involved in a range of cellular responses including cellgrowth, differentiation, and apoptosis (Parker et al (1995) CurrentBiology, 5:577-99; Yao et al (1995) Science, 267:2003-05). Though thedownstream targets of phosphorylated lipids generated following PI3kinase activation have not been well characterized, emerging evidencesuggests that pleckstrin-homology domain- and FYVE-fingerdomain-containing proteins are activated when binding to variousphosphatidylinositol lipids (Sternmark et al (1999) J Cell Sci,112:4175-83; Lemmon et al (1997) Trends Cell Biol, 7:237-42). In vitro,some isoforms of protein kinase C(PKC) are directly activated by PIP3,and the PKC-related protein kinase, PKB, has been shown to be activatedby PI3 kinase (Burgering et al (1995) Nature, 376:599-602).

PI3 kinase also appears involved in leukocyte activation. Ap85-associated PI3 kinase activity has been shown to physicallyassociate with the cytoplasmic domain of CD28, which is an importantcostimulatory molecule for the activation of T-cells in response toantigen (Pages et al (1994) Nature, 369:327-29; Rudd, (1996) Immunity4:527-34). Activation of T cells through CD28 lowers the threshold foractivation by antigen and increases the magnitude and duration of theproliferative response. These effects are linked to increases in thetranscription of a number of genes including interleukin-2 (IL2), animportant T cell growth factor (Fraser et al (1991) Science,251:313-16). Mutation of CD28 such that it can no longer interact withPI3 kinase leads to a failure to initiate IL2 production, suggesting acritical role for PI3 kinase in T cell activation.

Inhibition of class I PI3 kinase induces apoptosis, blocks tumor inducedangiogenesis in vivo, and increases the radiosensitivity of certaintumors. At least two compounds, LY294002 and wortmannin, have beenwidely used as PI3 kinase inhibitors. These compounds, however, arenonspecific PI3K inhibitors, as they do not distinguish among the fourmembers of Class I PI3 kinases. For example, the IC50 values ofwortmannin (U.S. Pat. No. 6,703,414) against each of the various Class IPI3 kinases are in the range of 1-10 nanomolar (nM). LY294002(2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) is a well knownspecific inhibitor of class I PI3 kinases and has anti-cancer properties(Chiosis et al (2001) Bioorganic & Med. Chem. Lett. 11:909-913; Vlahoset al (1994) J. Biol. Chem. 269(7):5241-5248; Walker et al (2000) Mol.Cell. 6:909-919; Fruman et al (1998) Ann Rev Biochem, 67:481-507).

Patent literature belonging to various research groups around the worldincludes several such patents and/or patent applications viz., U.S. Pat.Nos. 6,608,056; 6,608,053; 6,838,457; 6,770,641; 6,653,320; 6,403,588;WO 2004017950; US 2004092561; WO 2004007491; WO 2004006916; WO2003037886; US 2003149074; WO 2003035618; WO 2003034997; US 2003158212;EP 1417976; US 2004053946; JP 2001247477; JP 08175990; JP 08176070). WO97/15658, U.S. Pat. Nos. 7,173,029; 7,037,915;. 6,703,414; WO2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491;WO2004/006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO2003/034997; including p110 alpha binding activity US 2008/0207611; US2008/0039459; US 2008/0076768; WO 2008/073785; WO 2008/070740;US20090270430A1; US2006270673 A1; WO2009129211A1; US20090263398A1;US20090263397A1; WO2009129259A2; U.S. Pat. Nos. 7,605,160; 7,605,155;7,608,622; US20090270621; US20090270445; US20090247567A1; U.S. Pat. No.7,592,342; US20090239847A1; U.S. Pat. No. 7,595,320; US20090247538A1;US20090239936A1; U.S. Pat. No. 7,595,330; US20090239859A1;WO2009117482A1; WO2009117097A1; US20090247565A1; WO2009120094A2;US20090258852A1; U.S. Pat. No. 7,601,724; WO2009126635A1; U.S. Pat. Nos.7,601,718; 7,598,245; US20090239859A1; US20090247554; US20090238828;WO2009114874A2; WO2009114870A2; US20090234132A1; WO2009112565A1;US20090233950A1; US20090233926A1; U.S. Pat. No. 7,589,101;WO2009111547A1; WO2009111531A1; WO2009109867A2 and WO2009105712A1.

reviews and studies regarding PI3K and related protein kinase pathwayshave been given by Pixu Liu et. al. (Nature Reviews Drug Discovery,2009, 8, 627-644); Nathan T. et. al. (Mol Cancer Ther., 2009; 8 (1)January, 2009); Romina Marone et, al. (Biochimica et Biophysica Acta1784 (2008) 159-185) and B. Markman et. al. (Annals of oncology Advanceaccess published August 2009). All of these patents and/or patentapplications and literature disclosures are incorporated herein asreference in their entirety for all purposes.

Despite the advances made in the area of kinases and in particular therole that PI3K and related protein kinases play in human diseases,challenges remain in terms of the complexities of the target involved,the protein structure of the kinases, specificity issues for variouskinase inhibitors, side effects and desired clinical benefits expectedform the PI3K inhibitors. Accordingly, there still remains an unmet anddire need for small molecule kinase modulators in order to regulateand/or modulate transduction of kinases, particularly PI3K and relatedprotein kinase for the treatment of diseases and disorders associatedwith kinases-mediated events.

SUMMARY OF INVENTION

The present invention is directed to compounds, which are useful as PI3Kprotein kinase modulators and in particular as PI3K inhibitors. In oneembodiment, the compound of the present invention has the formula:

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein

-   -   each occurrence of R is independently selected from hydrogen,        halogen, —OR^(a), CN, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted C₂₋₆ alkenyl, substituted or        unsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₃₋₈        cycloalkyl, and substituted or unsubstituted heterocyclic group;    -   R¹ and R² may be the same or different and are independently        selected from hydrogen, halogen, and substituted or        unsubstituted C₁₋₆ alkyl, or both R¹ and R² directly bound to a        common atom, may be joined to form an oxo group (═O) or a        substituted or unsubstituted saturated or unsaturated 3-10        member ring (including the carbon atom to which R¹ and R² are        bound), which may optionally include one or more heteroatoms        which may be the same or different and are selected from O,        NR^(a) and S;    -   Cy¹ is a monocyclic group selected from substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocyclic group, substituted or unsubstituted aryl and        substituted or unsubstituted heteroaryl;    -   Cy² is selected from a substituted or unsubstituted heterocyclic        group, substituted or unsubstituted aryl and substituted or        unsubstituted heteroaryl;    -   L₁ is absent or selected from —(CR^(a)R^(b))_(q)—, —O—,        —S(═O)_(q)—, —NR^(a)— or —C(═Y)—.    -   each occurrence of R^(a) and R^(b) may be the same or different        and are independently selected from hydrogen, halogen, hydroxy,        cyano, substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d)        (wherein R^(c) and R^(d) are independently hydrogen, halogen,        hydroxy, cyano, substituted or unsubstituted (C₁₋₆)alkyl, and        (C₁₋₆)alkoxy) and —OR^(c) (wherein R^(c) is substituted or        unsubstituted (C₁₋₆)alkyl) or when R^(a) and R^(b) are directly        bound to a common atom, they may be joined to form an oxo group        (═O) or form a substituted or unsubstituted saturated or        unsaturated 3-10 member ring (including the common atom to which        R^(a) and R^(b) are directly bound), which may optionally        include one or more heteroatoms which may be the same or        different and are selected from O, NR^(d) (wherein R^(d) is        hydrogen or substituted or unsubstituted (C₁₋₆)alkyl) or S;    -   Y is selected from O, S, and NR^(a);    -   n is an integer from 1 to 4; and    -   q is 0, 1 or 2.    -   Yet another embodiment is a compound having the formula (I-A) or        (I-B)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein

-   -   R is independently selected from hydrogen, halogen, —OR^(a), CN,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, substituted or unsubstituted C₃₋₈ cycloalkyl, and        substituted or unsubstituted heterocyclic group;    -   R¹ and R² may be the same or different and are independently        selected from hydrogen, halogen, and substituted or        unsubstituted C₁₋₆ alkyl or both R¹ and R² directly bound to a        common atom, may be joined to form an oxo group (═O) or may be        joined to form a substituted or unsubstituted saturated or        unsaturated 3-10 member ring (including the common atom to which        R¹ and R² are directly bound), which may optionally include one        or more heteroatoms which may be the same or different and are        selected from O, NR^(a) and S;    -   Cy¹ is a monocyclic group selected from substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocyclic group, substituted or unsubstituted aryl and        substituted or unsubstituted heteroaryl;    -   Cy² is selected from substituted or unsubstituted heterocyclic        group and substituted or unsubstituted heteroaryl.    -   L₁ is absent or selected from —(CR^(a)R^(b))_(q)—, —O—,        —S(═O)_(q), —NR^(a)— or —C(═Y)—.    -   each occurrence of R^(a) and R^(b) may be the same or different        and are independently selected from hydrogen, halogen, hydroxy,        cyano, substituted or unsubstituted (C₁₋₆)alkyl, —NR^(c)R^(d)        (wherein R^(c) and R^(d) are independently hydrogen, halogen,        hydroxy, cyano, substituted or unsubstituted (C₁₋₆)alkyl, and        (C₁₋₆)alkoxy) and —OR^(c) (wherein R^(c) is substituted or        unsubstituted (C₁₋₆)alkyl) or when R^(a) and R^(b) are directly        bound to a common atom, they may be joined to form an oxo group        (═O) or form a substituted or unsubstituted saturated or        unsaturated 3-10 member ring (including the common atom to which        R^(a) and R^(b) are directly bound), which may optionally        include one or more heteroatoms which may be the same or        different and are selected from O, NR^(d) (wherein R^(d) is        hydrogen or substituted or unsubstituted (C₁₋₆)alkyl) or S;    -   Y is selected from O, S, and NR^(a); and    -   q is 0, 1 or 2.

Yet another embodiment is a compound having the formula (I), (I-A), or(I-B) wherein R is selected from hydrogen, halogen, substituted orunsubstituted C₁₋₆ alkyl or OR^(a).

Yet another embodiment is a compound having the formula (I), (I-A), or(I-B) wherein R is selected from hydrogen, halogen or OR^(a).

Further preferred is a compound having the formula (I), (I-A), or (I-B)wherein Cy¹ is selected from substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl.

Illustrative examples of optionally substituted Cy¹ groups include thoseshown below:

Further preferred is a compound having the formula (I) wherein Cy¹ isselected from

Further preferred is a compound having the formula (I) wherein Cy¹ issubstituted or unsubstituted phenyl

Further preferred is a compound having the formula (I) wherein Cy¹ issubstituted phenyl.

Further preferred is a compound having the formula (I) wherein Cy is2-methyl phenyl or 3-fluoro phenyl.

Yet another embodiment is a compound having the formula (I) wherein R¹and R² independently represent hydrogen or substituted or unsubstitutedC₁₋₆ alkyl.

Yet another embodiment is a compound having the formula (I) wherein L₁is selected from —S(═O)_(q) or —NR^(a)—.

Yet another embodiment is a compound having the formula (I) wherein q is0.

Yet another embodiment is a compound having the formula (I) wherein L₁is absent.

Yet another embodiment, is a compound having the formula (I) wherein Cy²is selected from

Yet another embodiment, is a compound having the formula (I) wherein Cy²is selected from

wherein

-   -   X is CR³; and    -   R³ is independently selected from hydrogen, hydroxy, halogen,        carboxyl, cyano, nitro, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted cycloalkyl, substituted        or unsubstituted cycloalkenyl, substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl, substituted        heterocyclylalkyl ring, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted heterocyclic ring,        substituted or unsubstituted guanidine, —COOR^(x), —C(O)R^(x),        —C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(y)R^(z),        —NR^(x)CONR^(y)R^(z), —N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y),        -(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y), —NR^(x)R^(y),        —NR^(x)C(O)R^(y)—, —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z),        —SONR^(x)R^(y)—, —SO₂NR^(x)R^(y)—, —OR^(x),        —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—, —OC(O)R^(x),        —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),        —R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),        —R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), —ONO₂, wherein        R^(x), R^(y) and R^(z) in each of the above groups can be        hydrogen, substituted or unsubstituted alkyl, substituted or        unsubstituted alkoxy, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, substituted or        unsubstituted aryl, substituted or unsubstituted arylalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloalkenyl, substituted or unsubstituted amino,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, substituted heterocyclylalkyl ring, substituted or        unsubstituted heteroarylalkyl, or substituted or unsubstituted        heterocyclic ring, or any two of R^(x), R^(y) and R^(z) may be        joined to form a substituted or unsubstituted saturated or        unsaturated 3-10 membered ring, which may optionally include        heteroatoms which may be the same or different and are selected        from O, NR^(X) or S.

For example, Cy² represented as formula a, b c, d or e above can be

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III) or (IA-IV)

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof,wherein:

-   -   each occurrence of R is independently selected from hydrogen,        halogen, —OR^(a), CN, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted C₂₋₆ alkenyl, substituted or        unsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₃₋₈        cycloalkyl, and substituted or unsubstituted heterocyclic group;    -   R¹ and R² may be the same or different and are independently        selected from hydrogen, halogen, and substituted or        unsubstituted C₁₋₆ alkyl or both R¹ and R² directly bound to a        common atom, may be joined to form an oxo group (═O) or may be        joined to form a substituted or unsubstituted saturated or        unsaturated 3-10 member ring (including the common atom to which        R¹ and R² are directly bound), which may optionally include one        or more heteroatoms which may be the same or different and are        selected from O, NR^(a) and S;    -   Cy¹ is a monocyclic group selected from substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocyclic group, substituted or unsubstituted aryl and        substituted or unsubstituted heteroaryl;    -   each occurrence of X is independently selected from CR³ or N;    -   each occurrence of R³ is independently selected from hydrogen,        hydroxy, halogen, carboxyl, cyano, nitro, substituted or        unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted arylalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted heterocyclic ring,        substituted heterocyclylalkyl ring, substituted or unsubstituted        guanidine, —COOR^(x), —C(O)R^(x), —C(S)R^(x), —C(O)NR^(x)R^(y),        —C(O)ONR^(x)R^(y), —NR^(y)R^(z), —NR^(x)CONR^(y)R^(z),        —N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), -(═N—N(R^(x))R^(y)),        —NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,        —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,        —SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z),        —OR^(x)C(O)OR^(y)—, —OC(O)R^(x), —OC(O)NR^(x)R^(y),        —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y), —R^(x)C(O)OR^(y),        —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x), —R^(x)OC(O)R^(y),        —SR^(x), —SOR^(x), —SO₂R^(x), and —ONO₂, wherein R^(x), R^(y)        and R^(z) in each of the above groups can be hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted arylalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heteroarylalkyl, substituted or unsubstituted        heterocyclic ring, substituted or unsubstituted        heterocyclylalkyl ring, or substituted or unsubstituted amino,        or any two of R^(x), R^(y) and R^(z) may be joined to form a        substituted or unsubstituted saturated or unsaturated 3-10        membered ring, which may optionally include heteroatoms which        may be the same or different and are selected from O, NR^(x)        (e.g., R^(x) can be hydrogen or substituted or unsubstituted        alkyl) or S.    -   n is an integer from 1 to 4; and    -   q is 0, 1 or 2.

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III) or (IA-IV) wherein R is selected from hydrogen, halogen,substituted or unsubstituted C₁₋₆ alkyl or OR^(a).

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III) or (IA-IV) wherein R is selected from hydrogen, halogen orOR^(a).

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III) or (IA-IV) wherein Cy¹ is selected from

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III) or (IA-IV) wherein n is 1.

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III) or (IA-IV) wherein R¹ and R² independently represent hydrogenor substituted or unsubstituted C₁₋₆ alkyl.

Yet another embodiment is a compound having the formula (IA-II) whereinR³ is selected from iodo, cyano, substituted or unsubstituted alkynyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

Yet another embodiment is a compound having the formula (IA-II) whereinR³ is selected from substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

Yet another embodiment is a compound having the formula (IA-II) whereinR³ is selected from

wherein

-   -   each occurrence of X is independently CR⁴ or N;    -   X¹ is O, S, or NR⁴; and    -   each occurrence of R⁴ is independently selected from hydrogen,        hydroxy, halogen, carboxyl, cyano, nitro, substituted or        unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted arylalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl        substituted or unsubstituted cycloalkenyl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted heterocyclic ring,        substituted heterocyclylalkyl ring, substituted or unsubstituted        guanidine, —COOR^(x), —C(O)R^(x), —C(S)R^(x), —C(O)NR^(x)R^(y),        —C(O)ONR^(x)R^(y), —NR^(y)R^(z), —NR^(x)CONR^(y)R^(z),        —N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), -(═N—N(R^(x))R^(y)),        —NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,        —NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,        —SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z),        —OR^(x)C(O)OR^(y)—, —OC(O)R^(x), —OC(O)NR^(x)R^(y),        —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y), —R^(x)C(O)OR^(y),        —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x), —R^(x)OC(O)R^(y),        —SR^(x), —SOR^(x), —SO₂R^(x), and —ONO₂, wherein R^(x), R^(y)        and R^(z) in each of the above groups can be hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted arylalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        cycloalkylalkyl, substituted or unsubstituted cycloalkenyl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heteroarylalkyl, substituted or unsubstituted        heterocyclic ring, substituted or unsubstituted        heterocyclylalkyl ring, or substituted or unsubstituted amino,        or any two of R^(x), R^(y) and R^(z) may be joined to form a        substituted or unsubstituted saturated or unsaturated 3-10        membered ring, which may optionally include heteroatoms which        may be the same or different and are selected from O, NR^(x)        (e.g., Rx can be hydrogen or substituted or unsubstituted alkyl)        or S.

For example, R³ can be any one of the following:

Yet another embodiment is a compound having the formula (IA-II) whereinR³ is selected from

Yet another embodiment is a compound having the formula (IA-I), (IA-II),(IA-III) and (IA-IV) wherein X is CR³ and each occurrence of R³ isindependently hydrogen, halogen, hydroxyl or NH₂.

Yet another embodiment is a compound of formula (IA-V)

or a pharmaceutically acceptable salt thereof, wherein

-   -   R, R¹, R², R³ and X are as defined above with respect to any of        formulas (I), (I-A), (I-B), (IA-I) and (IA-II);    -   each occurrence of R⁵ is hydrogen, C₁₋₆ alkyl or halogen; and    -   p is 0, 1, 2, 3, 4 or 5.

Yet another embodiment is a compound having the formula (IA-V) wherein nis 0.

Yet another embodiment is a compound having the formula (IA-V) wherein nis 1 and R is halogen (such as fluoro).

Yet another embodiment is a compound having the formula (IA-V) wherein pis 0.

Yet another embodiment is a compound having the formula (IA-V) wherein pis 1 and R⁵ is 3-fluoro or 2-methyl.

Yet another embodiment is a compound having the formula (IA-V) whereinR¹ is methyl and R² is hydrogen.

Yet another embodiment is a compound having the formula (IA-V) whereinR¹ is ethyl and R² is hydrogen.

Yet another embodiment is a compound having the formula (IA-V) whereinR¹ and R² are hydrogen.

Yet another embodiment is a compound having the formula (IA-V) whereinR³ is.

Yet another embodiment is a compound having the formula (IA-V) wherein Xis C—H, C—F, C—Cl, C—NH₂ or C—OH.

Further preferred is a compound having the formula (IA-V) wherein X isC—H.

Yet another embodiment is a compound of formula (IA-VI)

or a pharmaceutically acceptable salt thereof, wherein

-   -   R, R¹, R² and X are as defined above with respect to any of        formulas (I), (I-A), (I-B) and (IA-III);    -   each occurrence of R⁵ is hydrogen, C₁₋₆ alkyl or halogen; and    -   p is 0, 1, 2, 3, 4 or 5.

Yet another embodiment is a compound having the formula (IA-VI) whereinn is 0.

Yet another embodiment is a compound having the formula (IA-VI) whereinn is 1 and R is halogen (such as fluoro).

Yet another embodiment is a compound having the formula (IA-VI) whereinp is 0.

Yet another embodiment is a compound having the formula (IA-VI) whereinp is 1 and R⁵ is 3-fluoro or 2-methyl.

Yet another embodiment is a compound having the formula (IA-VI) whereinR¹ is methyl and R² is hydrogen.

Yet another embodiment is a compound having the formula (IA-VI) whereinR¹ is ethyl and R² is hydrogen.

Yet another embodiment is a compound having the formula (IA-VI) whereinR¹ and R² are hydrogen.

Yet another embodiment is a compound having the formula (IA-VI) whereineach occurrence of X is independently selected from C—H, C—F, C—Cl,C—NH₂ or C—OH.

Further preferred is a compound having the formula (IA-VI) wherein X isC—H.

Representative compounds of the present invention include thosespecified below (including in Table 1) and pharmaceutically acceptablesalts thereof. The present invention should not be construed to belimited to them.

-   2-[(6-Amino-9H-purin-9-yl)methyl]-6-bromo-3-phenyl-4H-chromen-4-one;-   6-Bromo-2-(morpholinomethyl)-3-phenyl-4H-chromen-4-one;-   6-Bromo-2-(morpholinomethyl)-3-phenyl-4H-chromen-4-one    hydrochloride;-   2-[(6-Amino-9H-purin-9-yl)methyl]-3-phenyl-4H-chromen-4-one;-   2-(Morpholinomethyl)-3-phenyl-4H-chromen-4-one;-   2-(Morpholinomethyl)-3-phenyl-4H-chromen-4-one hydrochloride;-   2-[(1H-Benzo[d]imidazol-1-yl)methyl]-6-bromo-3-phenyl-4H-chromen-4-one;-   6-Bromo-2-[(4-methyl-1H-benzo[d]imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one;-   2-[(1H-benzo[d]imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one;-   2-[(4-methyl-1H-benzo[d]imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one;-   2-[(6-Chloro-9H-purin-9-yl)methyl]-3-phenyl-4H-chromen-4-one;-   6-Bromo-2-[(6-chloro-9H-purin-9-yl)methyl]-3-phenyl-4H-chromen-4-one;-   2-((9H-Purin-6-ylthio)methyl)-3-phenyl-4H-chromen-4-one;-   2-[(1H-Imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one;-   2-[(9H-Purin-6-ylthio)methyl]-6-bromo-3-phenyl-4H-chromen-4-one;-   2-((4-Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-bromo-3-phenyl-4H-chromen-4-one;-   2-[(6-Amino-9H-purin-9-yl)methyl]-6-bromo-3-(4-fluorophenyl)-4H-chromen-4-one;-   2-[(6-Amino-9H-purin-9-yl)methyl]-3-(4-fluorophenyl)-4H-chromen-4-one;-   6-Bromo-3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one;-   6-Bromo-3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one    hydro chloride;-   3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one;-   3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one    hydrochloride;-   2-[(6-Amino-9H-purin-9-yl)methyl]-6-bromo-3-o-tolyl-4H-chromen-4-one;-   7-[(6-Bromo-4-oxo-3-phenyl-4H-chromen-2-yl)methyl]-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione;-   2-(1-(6-Amino-9H-purin-9-yl)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;-   2-(1-(9H-Purin-6-ylthio)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-phenyl-4H-chromen-4-one;-   (S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;-   2-((9H-purin-6-ylamino)methyl)-6-bromo-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;-   2-((6-Amino-9H-purin-9-yl)methyl)-6-methoxy-3-phenyl-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)ethyl)-6-bromo-3-(2-fluorophenyl)-4H-chromen-4-one;-   2-((6-Amino-9H-purin-9-yl)methyl)-6-bromo-3-(2-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl) propyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((6-Amino-9H-purin-9-yl)methyl)-3-(2-fluorophenyl)-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-(2-fluorophenyl)-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)propyl)-3-(2-fluorophenyl)-4H-chromen-4-one;-   2-(1-(6-amino-9H-purin-9-yl)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)propyl)-3-(4-fluorophenyl)-4H-chromen-4-one;-   2-(1-(6-amino-9H-purin-9-yl)propyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-(4-fluorophenyl)-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   2-(1-(4-Amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one;-   2-((9H-purin-6-ylamino)methyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-o-tolyl-4H-chromen-4-one;-   2-((9H-purin-6-ylamino)methyl)-3-(2-fluorophenyl)-4H-chromen-4-one;-   2-((9H-purin-6-ylamino)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(6-amino-9H-purin-9-yl)ethyl)-6-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one;-   2-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-(3,5-difluorophenyl)-4H-chromen-4-one;-   2-(1-(6-amino-9H-purin-9-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-Amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   (R)-2-(1-(9H-purin-6-ylamino)    ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   (S)-2-(1-(9H-purin-6-ylamino)    ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   2-((4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)    propyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-amino-3-(3-hydroxyprop-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-amino-3-(3-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-amino-3-(1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one-   2-((4-amino-3-(3-hydroxypropyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   N-(3-(4-amino-1-((4-oxo-3-phenyl-4H-chromen-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetamide;-   2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-(1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   (S)-2-(1-(9H-purin-6-ylamino) ethyl)-3-phenyl-4H-chromen-4-one;-   (S)-2-(1-(9H-purin-6-ylamino)    ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-fluoro-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-hydroxyprop-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-chloro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-chloro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((6-amino-9H-purin-9-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-fluoro-2-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(3-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-((4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-(2-aminopyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(1H-indol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-chloro-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-chloro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2-chloro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2-chloro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(1H-indol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-Amino-3-(3-methyl-1H-indol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   tert-butyl-(5-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophen-2-yl)methylcarbamate-   2-(1-(4-amino-3-(5-(aminomethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methyl-1H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   N-(4-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetamide;-   2-(1-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2,3-dihydrobenzofuran-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-ethyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methyl-1H-indol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   4-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2-carbaldehyde;-   2-(1-(4-amino-3-(5-(hydroxymethyl)thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)    propyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methyl-1H-indol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((6-amino-9H-purin-9-yl)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   2-((6-amino-9H-purin-9-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((9H-purin-6-ylamino)    methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((9H-purin-6-ylamino) methyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   (R)-2-(1-(9H-purin-6-ylamino)    ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one;-   2-(1-(4-amino-3-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-((4-amino-3-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;-   (+)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   (−)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-methoxy-3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2-fluoro-5-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(dibenzo[b,d]furan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-(benzyloxy)-3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-(dimethylamino)    phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-ethoxy-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(3-(4-acetylphenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-(benzyloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-(dimethylamino)    phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-ethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(benzo[b]thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(5-chlorothiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3,5-dimethylisoxazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-propoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(4-ethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-chloro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(6-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-(methoxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(6-hydroxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   6-Fluoro-3-(3-fluorophenyl)-2-(1-(4-methoxyphenylamino)    ethyl)-4H-chromen-4-one;-   2-(1-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-Chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(1,3-dimethyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2,3-dimethyl-2H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(6-methoxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(benzo[b]thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(2,4-dimethoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   3-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropylbenzamide;-   2-(1-(4-amino-3-(3-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;-   2-(1-(4-amino-3-(3-(difluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;    and-   5-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)    furan-2-carbaldehyde;    and pharmaceutically acceptable salts thereof

TABLE 1 Ex. Structure  1

 2

 2a

 3

 4

 4a

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 17a

 18

 18a

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 51a

 52

 53

 54

 55

 56

 57

 57a

 57b

 57c

 57d

 57e

 57f

 57g

 58

 59

 60

 61

 62

 63

 64

 65

 66

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Yet another embodiment of the present invention is a method forinhibiting PI3K in a patient by administering to the patient aneffective amount of at least one compound of the present invention (forinstance, a compound of formula (I), (I-A), (I-B), (IA-I), (IA-II)(IA-III), (IA-IV), (IA-V) or (IA-VI) as defined above).

Yet another embodiment of the present invention is a method for treatinga proliferative disease via modulation of a protein kinase (such asPI3K) by administering to a patient in need of such treatment aneffective amount of at least one compound of the present invention. Inone embodiment, the compound of the present invention inhibits a proteinkinase (such as PI3K).

Yet another embodiment of the present invention is a method for treatinga proliferative disease via modulation of a protein kinase (such asPI3K) by administering to a patient in need of such treatment aneffective amount of at least one compound of the present invention, incombination (simultaneously or sequentially) with at least one otheranti-cancer agent. In one embodiment, the compound of formula (I),(I-A), (I-B), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V) or (IA-VI)inhibits a protein kinase (such as PI3K).

More particularly, the compounds of formula ((I), (I-A), (I-B), (IA-I),(IA-II), (IA-III), (IA-IV), (IA-V) or (IA-VI) and pharmaceuticallyacceptable esters or salts thereof can be administered for thetreatment, prevention and/or amelioration of PI3K and related proteinkinase mediated diseases or disorders, including but not limited to,cancer and other proliferative diseases or disorders.

The compounds of the present invention are useful in the treatment of avariety of cancers, including, but not limited to, the following:

-   -   carcinoma, including that of the bladder, breast, colon, kidney,        liver, lung, including small cell lung cancer, esophagus, gall        bladder, ovary, pancreas, stomach, cervix, thyroid, prostate,        and skin, including squamous cell carcinoma;    -   hematopoietic tumors of lymphoid lineage, including leukemia,        acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell        lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins        lymphoma, hairy cell lymphoma and Burkett's lymphoma;    -   hematopoietic tumors of myeloid lineage, including acute and        chronic myelogenous leukemias, myelodysplastic syndrome and        promyelocytic leukemia;    -   tumors of mesenchymal origin, including fibrosarcoma and        rhabdomyosarcoma;    -   tumors of the central and peripheral nervous system, including        astrocytoma, neuroblastoma, glioma and schwannomas; and    -   other tumors, including melanoma, seminoma, teratocarcinoma,        osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid        follicular cancer and Kaposi's sarcoma.

Due to the key role of protein kinases in the regulation of cellularproliferation in general, the protein kinase inhibitors of the presentinvention could act as reversible cytostatic agents which may be usefulin the treatment of any disease process which features abnormal cellularproliferation, e.g., benign prostatic hyperplasia, familial adenomatosispolyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis,arthritis, psoriasis, glomerulonephritis, restenosis followingangioplasty or vascular surgery, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, endotoxic shock,and fungal infections.

The compounds of the present invention as modulators of apoptosis areuseful in the treatment of cancer (including but not limited to thosetypes mentioned herein above), viral infections (including but notlimited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus andadenovirus), prevention of AIDS development in HIV-infected individuals,autoimmune diseases (including but not limited to systemic lupus,erythematosus, autoimmune mediated glomerulonephritis, rheumatoidarthritis, psoriasis, inflammatory bowel disease, and autoimmunediabetes mellitus), neurodegenerative disorders (including but notlimited to Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinalmuscular atrophy and cerebellar degeneration), myelodysplasticsyndromes, aplastic anemia, ischemic injury associated with myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, hematological diseases(including but not limited to chronic anemia and aplastic anemia),degenerative diseases of the musculoskeletal system (including but notlimited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis,cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

The compounds of present invention can modulate the level of cellularRNA and DNA synthesis. These agents are therefore useful in thetreatment of viral infections (including but not limited to HIV, humanpapilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbisvirus and adenovirus).

The compounds of the present invention are useful in the chemopreventionof cancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse. The compounds are alsouseful in inhibiting tumor angiogenesis and metastasis. One embodimentof the invention is a method of inhibiting tumor angiogenesis ormetastasis in a patient in need thereof by administering an effectiveamount of one or more compounds of the present invention.

Another embodiment of the present invention is a method of treating animmune system-related disease (e.g., an autoimmune disease), a diseaseor disorder involving inflammation (e.g., asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, inflammatory bowel disease,glomerulonephritis, neuroinflammatory diseases, multiple sclerosis,uveitis and disorders of the immune system), cancer or otherproliferative disease, a hepatic disease or disorder, a renal disease ordisorder. The method includes administering an effective amount of oneor more compounds of the present invention.

Examples of immune disorders include psoriasis, rheumatoid arthritis,vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis,asthma, inflammatory muscle disease, allergic rhinitis, vaginitis,interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic orxenogeneic transplantation (organ, bone marrow, stem cells and othercells and tissues) graft rejection, graft-versus-host disease, lupuserythematosus, inflammatory disease, type I diabetes, pulmonaryfibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g.,Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmunehemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsinghepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopicdermatitis.

In one embodiment, the compounds described herein are used asimmunosuppresants to prevent transplant graft rejections, allogeneic orxenogeneic transplantation rejection (organ, bone marrow, stem cells,other cells and tissues), and graft-versus-host disease. In otherembodiments, transplant graft rejections result from tissue or organtransplants. In further embodiments, graft-versus-host disease resultsfrom bone marrow or stem cell transplantation. One embodiment is amethod of preventing or decreasing the risk of transplant graftrejection, allogeneic or xenogeneic transplantation rejection (organ,bone marrow, stem cells, other cells and tissues), or graft-versus-hostdisease by administering an effective amount of one or more compounds ofthe present invention.

The compounds of the present invention are also useful in combination(administered together or sequentially) with known anti-cancertreatments such as radiation therapy or with cytostatic or cytotoxic oranticancer agents, such as for example, but not limited to, DNAinteractive agents, such as cisplatin or doxorubicin; topoisomerase IIinhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11or topotecan; tubulin interacting agents, such as paclitaxel, docetaxelor the epothilones (for example ixabepilone), either naturally occurringor synthetic; hormonal agents, such as tamoxifen; thymidilate synthaseinhibitors, such as 5-fluorouracil; and anti-metabolites, such asmethotrexate, other tyrosine kinase inhibitors such as Iressa andOSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDKinhibitors; SRC inhibitors; c-Kit inhibitors; Her1/2 inhibitors andmonoclonal antibodies directed against growth factor receptors such aserbitux (EGF) and herceptin (Her2) and other protein kinase modulatorsas well.

The compounds of the present invention are also useful in combination(administered together or sequentially) with one or more steroidalanti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs)or Immune Selective Anti-Inflammatory Derivatives (ImSAIDs).

The invention further provides a pharmaceutical composition comprisingone or more compounds of the present invention (such as a compoundhaving formula (I), (I-A), (I-B), (IA-I), (IA-II), (IA-III), (IA-IV),(IA-V) or (IA-VI)) together with a pharmaceutically acceptable carrier.The pharmaceutical composition may further comprise one or more of theactive ingredients identified above, such as other anti-cancer agents.In one embodiment, the pharmaceutical composition includes atherapeutically effective amount of one or more compounds of formula(I), (I-A), (I-B), (IA-I), (IA-II) (IA-III), (IA-IV), (IA-V) or (IA-VI).

Yet another embodiment is a method of treating leukemia in a patient inneed thereof by administering a therapeutically effective amount of acompound of the present invention. For example, the compounds of thepresent invention are effective for treating chronic lymphocyticleukemia (CLL), non-Hodgkin lymphoma (NHL), acute myeloid leukemia(AML), multiple myeloma (MM), small lymphocytic lymphoma (SLL), andindolent non-Hodgkin's lymphoma (I-NHL).

Yet another embodiment is a method of treating allergic rhinitis in apatient in need thereof by administering a therapeutically effectiveamount of a compound of the present invention.

DETAILED DESCRIPTION

As used herein the following definitions shall apply unless otherwiseindicated. Further many of the groups defined herein can be optionallysubstituted. The listing of substituents in the definition is exemplaryand is not to be construed to limit the substituents defined elsewherein the specification.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl (t-butyl). The term “(C₁₋₆)alkyl” refers to an alkylgroup as defined above having up to 6 carbon atoms.

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched orbranched chain having about 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl(allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, and 2-butenyl. The term “(C₂₋₆)alkenyl” refers to an alkenylgroup as defined above having up to 6 carbon atoms.

The term “alkynyl” refers to a straight or branched chain hydrocarbylradical having at least one carbon-carbon triple bond, and having in therange of 2 to up to 12 carbon atoms (with radicals having in the rangeof 2 to up to 10 carbon atoms presently being preferred) e.g., ethynyl,propynyl, and butnyl. The term “(C₂₋₆) alkynyl” refers to an alkynylgroup as defined above having up to 6 carbon atoms.

The term “alkoxy” denotes an alkyl, cycloalkyl, or cycloalkylalkyl groupas defined above attached via an oxygen linkage to the rest of themolecule. The term “substituted alkoxy” refers to an alkoxy group wherethe alkyl constituent is substituted (i.e., —O-(substituted alkyl)wherein the term “substituted alkyl” is the same as defined above for“alkyl”. For example “alkoxy” refers to the group —O-alkyl, includingfrom 1 to 8 carbon atoms of a straight, branched, cyclic configurationand combinations thereof attached to the parent structure throughoxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,cyclopropyloxy, and cyclohexyloxy.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groupsinclude perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclicgroups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl. The term“(C₃₋₈) cycloalkyl” refers to a cycloalkyl group as defined above havingup to 8 carbon atoms.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radicalcontaining in the range of about 3 up to 8 carbon atoms directlyattached to an alkyl group which are then attached to the main structureat any carbon from the alkyl group that results in the creation of astable structure such as cyclopropylmethyl, cyclobutylethyl, andcyclopentylethyl.

The term “cycloalkenyl” refers to cyclic ring-containing radicalscontaining in the range of about 3 up to 8 carbon atoms with at leastone carbon-carbon double bond such as cyclopropenyl, cyclobutenyl, andcyclopentenyl. The term “cycloalkenylalkyl” refers to a cycloalkenylgroup directly attached to an alkyl group which are then attached to themain structure at any carbon from the alkyl group that results in thecreation of a stable structure.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 20 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl,indanyl, and biphenyl.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above, e.g., —CH₂C₆H₅ and —C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a non-aromatic 3 to 15 memberring radical which consists of carbon atoms and at least one heteroatomselected from nitrogen, phosphorus, oxygen and sulfur. For purposes ofthis invention, the heterocyclic ring radical may be a mono-, bi-, tri-or tetracyclic ring system, which may include fused, bridged or spiroring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfuratoms in the heterocyclic ring radical may be optionally oxidized tovarious oxidation states. In addition, the nitrogen atom may beoptionally quaternized. The heterocyclic ring radical may be attached tothe main structure at any heteroatom or carbon atom that results in thecreation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedabove. The heterocylcyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined above directly bonded to an alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure. Examplesof such heterocycloalkyl radicals include, but are not limited to,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiamorpholinyl.

The term “heteroaryl” refers to an optionally substituted 5 to 14 memberaromatic ring having one or more heteroatoms selected from N, O, and Sas ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ringsystem. Examples of such “heterocyclic ring” or “heteroaryl” radicalsinclude, but are not limited to, oxazolyl, thiazolyl, imidazolyl,pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl,indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl,isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl,oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl,oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radicalmay be attached to the main structure at any heteroatom or carbon atomthat results in the creation of a stable structure. The term“substituted heteroaryl” also includes ring systems substituted with oneor more oxide (—O—) substituents, such as pyridinyl N-oxides.

The term “heteroarylalkyl” refers to a heteroaryl ring radical asdefined above directly bonded to an alkyl group. The heteroarylalkylradical may be attached to the main structure at any carbon atom fromalkyl group that results in the creation of a stable structure.

The term “cyclic ring” refers to a cyclic ring containing 3 to 10 carbonatoms.

The term “substituted” unless otherwise specified, refers tosubstitution with any one or any combination of the followingsubstituents which may be the same or different and are independentlyselected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo(═O), thio (═S), substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted aryl, substitutedor unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heteroarylalkyl, substituted or unsubstitutedheterocyclic ring, substituted heterocyclylalkyl ring, substituted orunsubstituted guanidine, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), NR^(y)R^(z), —NR^(x)CONR^(y)R^(z),—N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), -(═N—N(R^(x))R^(y)),—NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), and —ONO₂, whereinR^(x), R^(y) and R^(z) in each of the above groups can be hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted amino, substituted orunsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl,substituted or unsubstituted heterocyclic ring, or substitutedheterocyclylalkyl ring, or any two of R^(x), R^(y) and R^(z) may bejoined to form a substituted or unsubstituted saturated or unsaturated3-10 membered ring, which may optionally include heteroatoms which maybe the same or different and are selected from O, NR^(x) (e.g., R^(x)can be hydrogen or C₁₋₆ alkyl) or S. Substitution or the combinations ofsubstituents envisioned by this invention are preferably those thatresult in the formation of a stable or chemically feasible compound. Theterm stable as used herein refers to the compounds or the structure thatare not substantially altered when subjected to conditions to allow fortheir production, detection and preferably their recovery, purificationand incorporation into a pharmaceutical composition. The substituents inthe aforementioned “substituted” groups cannot be further substituted.For example, when the substituent on “substituted alkyl” is “substitutedaryl”, the substituent on “substituted aryl” cannot be “substitutedalkenyl”.

The term “halo”, “halide”, or, alternatively, “halogen” means fluoro,chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

The term “protecting group” or “PG” refers to a substituent that isemployed to block or protect a particular functionality. Otherfunctional groups on the compound may remain reactive. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include, but are not limited to,acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl(CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitablehydroxy-protecting groups include, but are not limited to, acetyl andsilyl. A “carboxy-protecting group” refers to a substituent of thecarboxy group that blocks or protects the carboxy functionality.Suitable carboxy-protecting groups include, but are not limited to,—CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, -2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, andnitroethyl. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

Certain of the compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that can be defined, in terms of absolutestereochemistry, as (R)— or (S)—. The present chemical entities,pharmaceutical compositions and methods are meant to include all suchpossible isomers, including racemic mixtures, optically pure forms andintermediate mixtures. For instance, non-limiting examples ofintermediate mixtures include a mixture of isomers in a ratio of 10:90,13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)-isomers canbe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers.

The term “tautomers” refers to compounds, which are characterized byrelatively easy interconversion of isomeric forms in equilibrium. Theseisomers are intended to be covered by this invention. “Tautomers” arestructurally distinct isomers that interconvert by tautomerization.“Tautomerization” is a form of isomerization and includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order, often the interchange of a single bond with anadjacent double bond. Where tautomerization is possible (e.g. insolution), a chemical equilibrium of tautomers can be reached. Anexample of tautomerization is keto-enol tautomerization. A specificexample of keto-enol tautomerization is the interconversion ofpentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Anotherexample of tautomerization is phenol-keto tautomerization. A specificexample of phenol-keto tautomerization is the interconversion ofpyridin-4-ol and pyridin-4(1H)-one tautomers.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable examples of such groups unlessotherwise specified are halogen atoms and mesyloxy,p-nitrobenzensulphonyloxy and tosyloxy groups.

The term “prodrug” refers to a compound, which is an inactive precursorof a compound, converted into its active form in the body by normalmetabolic processes. Prodrug design is discussed generally in Hardma, etal. (Eds.), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion isprovided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol.14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press(1987). To illustrate, prodrugs can be converted into apharmacologically active form through hydrolysis of, for example, anester or amide linkage, thereby introducing or exposing a functionalgroup on the resultant product. The prodrugs can be designed to reactwith an endogenous compound to form a water-soluble conjugate thatfurther enhances the pharmacological properties of the compound, forexample, increased circulatory half-life. Alternatively, prodrugs can bedesigned to undergo covalent modification on a functional group with,for example, glucuronic acid, sulfate, glutathione, amino acids, oracetate. The resulting conjugate can be inactivated and excreted in theurine, or rendered more potent than the parent compound. High molecularweight conjugates also can be excreted into the bile, subjected toenzymatic cleavage, and released back into the circulation, therebyeffectively increasing the biological half-life of the originallyadministered compound.

The term “ester” refers to a compound, which is formed by reactionbetween an acid and an alcohol with elimination of water. An ester canbe represented by the general formula RCOOR′.

These prodrugs and esters are intended to be covered within the scope ofthis invention.

Additionally the instant invention also includes the compounds whichdiffer only in the presence of one or more isotopically enriched atomsfor example replacement of hydrogen with deuterium or tritium, or thereplacement of a carbon by ^(13C)- or ^(14C)-enriched carbon.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, and Mn; salts of organic bases such as N,N′-diacetylethylenediamine,glucamine, triethylamine, choline, hydroxide, dicyclohexylamine,metformin, benzylamine, trialkylamine, and thiamine; chiral bases suchas alkylphenylamine, glycinol, and phenyl glycinol; salts of naturalamino acids such as glycine, alanine, valine, leucine, isoleucine,norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, and serine; quaternaryammonium salts of the compounds of invention with alkyl halides, alkylsulphates such as MeI and (Me)₂SO₄; non-natural amino acids such asD-isomers or substituted amino acids; guanidine; and substitutedguanidine wherein the substituents are selected from nitro, amino,alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts andaluminum salts. Salts may include acid addition salts where appropriatewhich are sulphates, nitrates, phosphates, perchlorates, borates,hydrohalides, acetates, tartrates, maleates, citrates, fumarates,succinates, palmoates, methanesulphonates, benzoates, salicylates,benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary from, for example, between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) includes thoseembodiments, for example, an embodiment of any composition of matter,composition, method, or process, or the like, that “consist of” or“consist essentially of” the described features.

The following abbreviations and terms have the indicated meaningsthroughout: PI3-K=Phosphoinositide 3-kinase; PI=phosphatidylinositol;PDK=Phosphoinositide Dependent Kinase; DNA-PK=Deoxyribose Nucleic AcidDependent Protein Kinase; PTEN=Phosphatase and Tensin homolog deleted onchromosome Ten; PIKK=Phosphoinositide Kinase Like Kinase; AIDS=AcquiredImmuno Deficiency Syndrome; HIV=Human Immunodeficiency Virus; MeI=MethylIodide; POCl₃=Phosphorous Oxychloride; KCNS=Potassium IsoThiocyanate;TLC=Thin Layer Chromatography; MeOH=Methanol; and CHCl₃=Chloroform.

Abbreviations used herein have their conventional meaning within thechemical and biological arts.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompassesadministration of two or more agents to an animal so that both agentsand/or their metabolites are present in the animal at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, “treatment,” “treating,” or “ameliorating” are usedinterchangeably. These terms refers to an approach for obtainingbeneficial or desired results including but not limited to therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thepatient, notwithstanding that the patient may still be afflicted withthe underlying disorder. For prophylactic benefit, the compositions maybe administered to a patient at risk of developing a particular disease,or to a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “subject” or “patient” refers to an animal, such as a mammal,for example a human. The methods described herein can be useful in bothhuman therapeutics and veterinary applications. In some embodiments, thepatient is a mammal, and in some embodiments, the patient is human.

“Radiation therapy” means exposing a patient, using routine methods andcompositions known to the practitioner, to radiation emitters such asalpha-particle emitting radionuclides (e.g., actinium and thoriumradionuclides), low linear energy transfer (LET) radiation emitters(i.e. beta emitters), conversion electron emitters (e.g. strontium-89and samarium-153-EDTMP, or high-energy radiation, including withoutlimitation x-rays, gamma rays, and neutrons.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or indirect interaction with the target.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes, but is not limited to, any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, one or more suitablediluents, fillers, salts, disintegrants, binders, lubricants, glidants,wetting agents, controlled release matrices, colorants/flavoring,carriers, excipients, buffers, stabilizers, solubilizers, andcombinations thereof. Except insofar as any conventional media or agentis incompatible with the active ingredient, its use in the therapeuticcompositions of the invention is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

In some embodiments, one or more subject compounds bind specifically toa PI3 kinase or a protein kinase selected from the group consisting ofmTor, DNA-dependent protein kinase (Pubmed protein accession number(PPAN) AAA79184), AbI tyrosine kinase (CAA52387), Bcr-Abl, hemopoieticcell kinase (PPAN CAI19695), Src (PPAN CAA24495), vascular endothelialgrowth factor receptor 2 (PPAN ABB82619), epidermal growth factorreceptor (PPAN AG43241), EPH receptor B4 (PPAN EAL23820), stem cellfactor receptor (PPAN AAF22141), Tyrosine-protein kinase receptor TIE-2(PPAN Q02858), fms-related tyrosine kinase δ (PPAN NP_(—)004110),platelet-derived growth factor receptor alpha (PPAN NP_(—)990080), RET(PPAN CAA73131), and any other related protein kinases, as well as anyfunctional mutants thereof.

In some embodiments, the IC50 of a subject compound for pi 10α, pi 10β,pi 10γ, or pi 10δ is less than about 1 uM, less than about 100 nM, lessthan about 50 nM, less than about 10 nM, less than 1 nM or even lessthan about 0.5 nM. In some embodiments, the IC50 of a subject compoundfor mTor is less than about 1 uM, less than about 100 nM, less thanabout 50 nM, less than about 10 nM, less than 1 nM or even less thanabout 0.5 nM. In some other embodiments, one or more subject compoundsexhibit dual binding specificity and are capable of inhibiting a PI3kinase (e.g., a class I PI3 kinase) as well as a protein kinase (e.g.,mTor) with an IC50 value less than about 1 uM, less than about 100 nM,less than about 50 nM, less than about 10 nM, less than 1 nM or evenless than about 0.5 nM.

In some embodiments, the compounds of the present invention exhibit oneor more functional characteristics disclosed herein. For example, one ormore subject compounds bind specifically to a PI3 kinase. In someembodiments, the IC50 of a subject compound for pi 10α, pi 10β, pi 10γ,or pi 10δ is less than about 1 uM, less than about 100 nM, less thanabout 50 nM, less than about 10 nM, less than about 1 nM, less thanabout 0.5 nM, less than about 100 pM, or less than about 50 pM.

In some embodiments, one or more of the subject compounds mayselectively inhibit one or more members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase) with an IC50 value of about100 nM, 50 nM, 10 nM, 5 nM, 100 pM, 10 pM or 1 pM, or less as measuredin an in vitro kinase assay.

In some embodiments, one or more of the subject compound may selectivelyinhibit one or two members of type I or class I phosphatidylinositol3-kinases (PI3-kinase) consisting of PI3-kinase α, PI3-kinase β,PI3-kinase γ, and PI3-kinase δ. In some aspects, some of the subjectcompounds selectively inhibit PI3-kinase δ as compared to all other typeI PI3-kinases. In other aspects, some of the subject compoundsselectively inhibit PI3-kinase δ and PI3-kinase γ as compared to therest of the type I PI3-kinases. In yet other aspects, some of thesubject compounds selectively inhibit PI3-kinase α and PI3-kinase β ascompared to the rest of the type I PI3-kinases. In still yet some otheraspects, some of the subject compounds selectively inhibit PI3-kinase δand PI3-kinase α as compared to the rest of the type I PI3-kinases. Instill yet some other aspects, some of the subject compounds selectivelyinhibit PI3-kinase δ and PI3-kinase β as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase δ and PI3-kinase αas compared to the rest of the type I PI3-kinases, or selectivelyinhibit PI3-kinase α and PI3-kinase γ as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase γ and PI3-kinase βas compared to the rest of the type I PI3-kinases.

In yet another aspect, an inhibitor that selectively inhibits one ormore members of type I PI3-kinases, or an inhibitor that selectivelyinhibits one or more type I PI3-kinase mediated signaling pathways,alternatively can be understood to refer to a compound that exhibits a50% inhibitory concentration (IC50) with respect to a given type IPI3-kinase, that is at least at least 10-fold, at least 20-fold, atleast 50-fold, at least 100-fold, at least 1000-fold, or lower, than theinhibitor's IC50 with respect to the rest of the other type IPI3-kinases.

As used herein, the term “PI3-kinase δ selective inhibitor” generallyrefers to a compound that inhibits the activity of the PI3-kinase δisozyme more effectively than other isozymes of the PI3K family. API3-kinase δ selective inhibitor compound is therefore more selectivefor PI3-kinase δ than conventional PI3K inhibitors such as wortmanninand LY294002, which are “nonselective PI3K inhibitors.”

Inhibition of PI3-kinase S may be of therapeutic benefit in treatment ofvarious conditions, e.g., conditions characterized by an inflammatoryresponse including but not limited to autoimmune diseases, allergicdiseases, and arthritic diseases. Importantly, inhibition of PI3-kinaseδ function does not appear to affect biological functions such asviability and fertility.

“Inflammatory response” as used herein is characterized by redness,heat, swelling and pain (i.e., inflammation) and typically involvestissue injury or destruction. An inflammatory response is usually alocalized, protective response elicited by injury or destruction oftissues, which serves to destroy, dilute or wall off (sequester) boththe injurious agent and the injured tissue. Inflammatory responses arenotably associated with the influx of leukocytes and/or leukocyte (e.g.,neutrophil) chemotaxis. Inflammatory responses may result from infectionwith pathogenic organisms and viruses, noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponses to foreign antigens, and autoimmune diseases. Inflammatoryresponses amenable to treatment with the methods and compounds accordingto the invention encompass conditions associated with reactions of thespecific defense system as well as conditions associated with reactionsof the non-specific defense system.

The therapeutic methods of the invention include methods for theamelioration of conditions associated with inflammatory cell activation.“Inflammatory cell activation” refers to the induction by a stimulus(including but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including but not limited to,major histocompatibility antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (polymorphonuclear leukocytesincluding neutrophils, basophils, and eosinophils) mast cells, dendriticcells, Langerhans cells, and endothelial cells). It will be appreciatedby persons skilled in the art that the activation of one or acombination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory condition.

“Autoimmune disease” as used herein refers to any group of disorders inwhich tissue injury is associated with humoral or cell-mediatedresponses to the body's own constituents. “Transplant rejection” as usedherein refers-to any immune response directed against grafted tissue(including organs or cells (e.g., bone marrow), characterized by a lossof function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia). “Allergic disease” as used hereinrefers to any symptoms, tissue damage, or loss of tissue functionresulting from allergy. “Arthritic disease” as used herein refers to anydisease that is characterized by inflammatory lesions of the jointsattributable to a variety of etiologies. “Dermatitis” as used hereinrefers to any of a large family of diseases of the skin that arecharacterized by inflammation of the skin attributable to a variety ofetiologies.

As previously described, the term “PI3-kinase δ selective inhibitor”generally refers to a compound that inhibits the activity of thePI3-kinase δ isozyme more effectively than other isozymes of the PI3Kfamily. The relative efficacies of compounds as inhibitors of an enzymeactivity (or other biological activity) can be established bydetermining the concentrations at which each compound inhibits theactivity to a predefined extent and then comparing the results.Typically, the preferred determination is the concentration thatinhibits 50% of the activity in a biochemical assay, i.e., the 50%inhibitory concentration or “IC50”. IC50 determinations can beaccomplished using conventional techniques known in the art. In general,an IC50 can be determined by measuring the activity of a given enzyme inthe presence of a range of concentrations of the inhibitor under study.The experimentally obtained values of enzyme activity then are plottedagainst the inhibitor concentrations used. The concentration of theinhibitor that shows 50% enzyme activity (as compared to the activity inthe absence of any inhibitor) is taken as the IC50 value. Analogously,other inhibitory concentrations can be defined through appropriatedeterminations of activity. For example, in some settings it can bedesirable to establish a 90% inhibitory concentration, i.e., IC90, etc.

Accordingly, a PI3-kinase δ selective inhibitor alternatively can beunderstood to refer to a compound that exhibits a 50% inhibitoryconcentration (IC50) with respect to PITS-kinase δ, that is at least10-fold, in another aspect at least 20-fold, and in another aspect atleast 30-fold, lower than the IC50 value with respect to any or all ofthe other class I PI3K family members. In an alternative embodiment ofthe invention, the term PI3-kinase δ selective inhibitor can beunderstood to refer to a compound that exhibits an IC50 with respect toPI3-kinase δ that is at least 50-fold, in another aspect at least100-fold, in an additional aspect at least 200-fold, and in yet anotheraspect at least 500-fold, lower than the IC50 with respect to any or allof the other PI3K class I family members. A PI3-kinase δ selectiveinhibitor is typically administered in an amount such that itselectively inhibits PI3-kinase δ activity, as described above.

The methods of the invention may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human or in a subject's body. In this context, the methods ofthe invention may be used therapeutically or prophylactically in anindividual. “Ex vivo” or “In vitro” means outside of a livingindividual. Examples of ex vivo cell populations include in vitro cellcultures and biological samples including but not limited to fluid ortissue samples obtained from individuals. Such samples may be obtainedby methods known in the art. Exemplary biological fluid samples includeblood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samplesinclude tumors and biopsies thereof. In this context, the invention maybe used for a variety of purposes, including therapeutic andexperimental purposes. For example, the invention may be used ex vivo orin vitro to determine the optimal schedule and/or dosing ofadministration of a PI3-kinase δ selective inhibitor for a givenindication, cell type, individual, and other parameters. Informationgleaned from such use may be used for experimental or diagnosticpurposes or in the clinic to set protocols for in vivo treatment. Otherex vivo uses for which the invention may be suited are described belowor will become apparent to those skilled in the art.

Pharmaceutical Compositions

The invention provides a pharmaceutical composition comprising one ormore compounds of the present invention. The pharmaceutical compositionmay include one or more additional active ingredients as describedherein. The pharmaceutical composition may be administered for any ofthe disorders described herein

In some embodiments, the invention provides pharmaceutical compositionsfor treating diseases or conditions related to an undesirable,over-active, harmful or deleterious immune response in a mammal Suchundesirable immune response can be associated with or result in, e.g.,asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis,auto-immune diseases, rhuematoid arthritis, graft versus host disease,and lupus erythematosus. The pharmaceutical compositions of the presentinvention can be used to treat other respiratory diseases including butnot limited to diseases affecting the lobes of lung, pleural cavity,bronchial tubes, trachea, upper respiratory tract, or the nerves andmuscle for breathing.

In some embodiments, the invention provides pharmaceutical compositionsfor the treatment of disorders such as hyperproliferative disorderincluding but not limited to cancer such as acute myeloid leukemia,thymus, brain, lung, squamous cell, skin, eye, retinoblastoma,intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric,stomach, pancreatic, bladder, breast, cervical, head, neck, renal,kidney, liver, ovarian, prostate, colorectal, esophageal, testicular,gynecological, thyroid, CNS, PNS, AIDS related (e.g. Lymphoma andKaposi's Sarcoma) or Viral-Induced cancer. In some embodiments, thepharmaceutical composition is for the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The invention also relates to a composition for treating a diseaserelated to vasculogenesis or angiogenesis in a mammal which can manifestas tumor angiogenesis, chronic inflammatory disease such as rheumatoidarthritis, inflammatory bowel disease, atherosclerosis, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The invention also provides compositions for the treatment of liverdiseases (including diabetes), pancreatitis or kidney disease (includingproliferative glomerulonephritis and diabetes-induced renal disease) orpain in a mammal.

The invention further provides a composition for the prevention ofblastocyte implantation in a mammal

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentinvention as the active ingredient, or a pharmaceutically acceptablesalt, ester, or prodrug thereof. Where desired, the pharmaceuticalcompositions contain a compound of the present invention as the activeingredient or a pharmaceutically acceptable salt and/or coordinationcomplex thereof, and one or more pharmaceutically acceptable excipients,carriers, such as inert solid diluents and fillers, diluents, includingsterile aqueous solution and various organic solvents, permeationenhancers, solubilizers and adjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,the subject compounds and other agent(s) may be mixed into a preparationor both components may be formulated into separate preparations to usethem in combination separately or at the same time.

Methods include administration of an inhibitor by itself, or incombination as described herein, and in each case optionally includingone or more suitable diluents, fillers, salts, disintegrants, binders,lubricants, glidants, wetting agents, controlled release matrices,colorants/flavoring, carriers, excipients, buffers, stabilizers,solubilizers, and combinations thereof.

Preparations of various pharmaceutical compositions are known in theart. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, WilliamG, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill,2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, New York, 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all ofwhich are incorporated by reference herein in their entirety.

The compounds or pharmaceutical composition of the present invention canbe administered by any route that enables delivery of the compounds tothe site of action, such asoral routes, intraduodenal routes, parenteralinjection (including intravenous, intraarterial, subcutaneous,intramuscular, intravascular, intraperitoneal or infusion), topicaladministration (e.g. transdermal application), rectal administration,via local delivery by catheter or stent or through inhalation. Thecompounds can also be administered intraadiposally or intrathecally.

The compositions can be administered in solid, semi-solid, liquid orgaseous form, or may be in dried powder, such as lyophilized form. Thepharmaceutical compositions can be packaged in forms convenient fordelivery, including, for example, solid dosage forms such as capsules,sachets, cachets, gelatins, papers, tablets, capsules, suppositories,pellets, pills, troches, and lozenges. The type of packaging willgenerally depend on the desired route of administration. Implantablesustained release formulations are also contemplated, as are transdermalformulations.

Routes of Administration

In the methods according to the invention, the inhibitor compounds maybe administered by various routes. For example, pharmaceuticalcompositions may be for injection, or for oral, nasal, transdermal orother forms of administration, including, e.g., by intravenous,intradermal, intramuscular, intramammary, intraperitoneal, intrathecal,intraocular, retrobulbar, intrapulmonary (e.g., aerosolized drugs) orsubcutaneous injection (including depot administration for long termrelease e.g., embedded-under the-splenic capsule, brain, or in thecornea); by sublingual, anal, or vaginal administration, or by surgicalimplantation, e.g., embedded under the splenic capsule, brain, or in thecornea. The treatment may consist of a single dose or a plurality ofdoses over a period of time. In general, the methods of the inventioninvolve administering effective amounts of a modulator of the inventiontogether with one or more pharmaceutically acceptable diluents,preservatives, solubilizers, emulsifiers, adjuvants and/or carriers, asdescribed above.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, and adjuvants.

In one aspect, the invention provides methods for oral administration ofa pharmaceutical composition of the invention. Oral solid dosage formsare described generally in Remington's Pharmaceutical Sciences, supra atChapter 89. Solid dosage forms include tablets, capsules, pills, trochesor lozenges, and cachets or pellets. Also, liposomal or proteinoidencapsulation may be used to formulate the compositions (as, forexample, proteinoid microspheres reported in U.S. Pat. No. 4,925,673).Liposomal encapsulation may include liposomes that are derivatized withvarious polymers (e.g., U.S. Pat. No. 5,013,556). The formulation mayinclude a compound of the invention and inert ingredients which protectagainst degradation in the stomach and which permit release of thebiologically active material in the intestine.

Toxicity and therapeutic efficacy of the PI3-kinase δ selectivecompounds can be determined by standard pharmaceutical procedures incell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50 (the dosetherapeutically effective in 50% of the population). Additionally, thisinformation can be determined in cell cultures or experimental animalsadditionally treated with other therapies including but not limited toradiation, chemotherapeutic agents, photodynamic therapies,radiofrequency ablation, anti-angiogenic agents, and combinationsthereof.

The amount of the compound administered will be dependent on the mammalbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes may be used as appropriate. A single dose of a compound ofthe invention may also be used for treatment of an acute condition.

In practice of the methods of the invention, the pharmaceuticalcompositions are generally provided in doses ranging from 1 pgcompound/kg body weight to 1000 mg/kg, 0.1 mg/kg to 100 mg/kg, 0.1 mg/kgto 50 mg/kg, and 1 to 20 mg/kg, given in daily doses or in equivalentdoses at longer or shorter intervals, e.g., every other day, twiceweekly, weekly, or twice or three times daily. The inhibitorcompositions may be administered by an initial bolus followed by acontinuous infusion to maintain therapeutic circulating levels of drugproduct. Those of ordinary skill in the art will readily optimizeeffective dosages and administration regimens as determined by goodmedical practice and the clinical condition of the individual to betreated. The frequency of dosing will depend on the pharmacokineticparameters of the agents and the route of administration. The optimalpharmaceutical formulation will be determined by one skilled in the artdepending upon the route of administration and desired dosage [see, forexample, Remington's Pharmaceutical Sciences, pp. 1435-1712, thedisclosure of which is hereby incorporated by reference]. Suchformulations may influence the physical state, stability, rate of invivo release, and rate of in vivo clearance of the administered agents.Depending on the route of administration, a suitable dose may becalculated according to body weight, body surface area or organ size.Further refinement of the calculations necessary to determine theappropriate dosage for treatment involving each of the above mentionedformulations is routinely made by those of ordinary skill in the artwithout undue experimentation, especially in light of the dosageinformation and assays disclosed herein, as well as the pharmacokineticdata observed in human clinical trials. Appropriate dosages may beascertained by using established assays for determining blood leveldosages in conjunction with an appropriate physician considering variousfactors which modify the action of drugs, e.g., the drug's specificactivity, the severity of the indication, and the responsiveness of theindividual, the age, condition, body weight, sex and diet of theindividual, the time of administration and other clinical factors. Asstudies are conducted, further information will emerge regarding theappropriate dosage levels and duration of treatment for various diseasesand conditions capable of being treated with the methods of theinvention.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the agents of the invention may continue as long asnecessary. In some embodiments, an agent of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, an agent of the invention is administered for less than 28,14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of theinvention is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compounds of the invention may be administered in dosages. It isknown in the art that due to intersubject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of the invention may be found byroutine experimentation in light of the instant disclosure.

When a compound of the invention, is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The inhibitors of the invention may be covalently or noncovalentlyassociated with a carrier molecule including but not limited to a linearpolymer (e.g., polyethylene glycol, polylysine, dextran, etc.), abranched-chain polymer (see U.S. Pat. Nos. 4,289,872 and 5,229,490; PCTPublication No. WO 93/21259), a lipid, a cholesterol group (such as asteroid), or a carbohydrate or oligosaccharide. Specific examples ofcarriers for use in the pharmaceutical compositions of the inventioninclude carbohydrate-based polymers such as trehalose, mannitol,xylitol, sucrose, lactose, sorbitol, dextrans such as cyclodextran,cellulose, and cellulose derivatives. Also, the use of liposomes,microcapsules or microspheres, inclusion complexes, or other types ofcarriers is contemplated.

Other carriers include one or more water soluble polymer attachmentssuch as polyoxyethylene glycol, or polypropylene glycol as describedU.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and4,179,337. Still other useful carrier polymers known in the art includemonomethoxy-polyethylene glycol, poly-(N-vinyl pyrrolidone)-polyethyleneglycol, propylene glycol homopolymers, a polypropylene oxidelethyleneoxide co-polymer, polyoxyethylated polyols (e.g., glycerol) andpolyvinyl alcohol, as well as mixtures of these polymers.

Derivitization with bifunctional agents is useful for cross-linking acompound of the invention to a support matrix or to a carrier. One suchcarrier is polyethylene glycol (PEG). The PEG group may be of anyconvenient molecular weight and may be straight chain or branched. Theaverage molecular weight of the PEG can range from about 2 kDa to about100 kDa, in another aspect from about 5 kDa to about 50 kDa, and in afurther aspect from about 5 kDa to about 10 kDa. The PEG groups willgenerally be attached to the compounds of the invention via acylation,reductive alkylation, Michael addition, thiol alkylation or otherchemoselective conjugation/ligation methods through a reactive group onthe PEG moiety (e.g., an aldehyde, amino, ester, thiol, ci-haloacetyl,maleimido or hydrazino group) to a reactive group on the targetinhibitor compound (e.g., an aldehyde, amino, ester, thiol,a-haloacetyl, maleimido or hydrazino group). Cross-linking agents caninclude, e.g., esters with 4-azidosalicylic acid, homobifunctionalimidoesters, including disuccinimidyl esters such as3,3′-dithiobis(succinimidylpropionate), and bifunctional maleimides suchas bis-N-maleimido-1,8-octane. Derivatizing agents such asmethyl-3-[(p-azidophenyl)dithiolpropioimidate yield photoactivatableintermediates that are capable of forming crosslinks in the presence oflight. Alternatively, reactive water-insoluble matrices such as cyanogenbromide-activated carbohydrates and the reactive substrates described inU.S. Pat. Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537;and 4,330,440 may be employed for inhibitor immobilization.

Method of Treatment

The invention also provides methods of using the compounds orpharmaceutical compositions of the present invention to treat diseaseconditions, including but not limited to diseases associated withmalfunctioning of one or more types of PI3 kinase. A detaileddescription of conditions and disorders mediated by pi 10δ kinaseactivity is set forth in WO 2001/81346 and US 2005/043239, both of whichare incorporated herein by reference in their entireties for allpurposes.

The treatment methods provided herein comprise administering to thesubject a therapeutically effective amount of a compound of theinvention. In one embodiment, the present invention provides a method oftreating an inflammation disorder, including autoimmune diseases in amammal. The method comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof.

The disorders, diseases, or conditions treatable with a compoundprovided herein, include, but are not limited to,

-   -   inflammatory or allergic diseases, including systemic        anaphylaxis and hypersensitivity disorders, atopic dermatitis,        urticaria, drug allergies, insect sting allergies, food        allergies (including celiac disease and the like), anaphylaxis,        serum sickness, drug reactions, insect venom allergies,        hypersensitivity pneumonitis, angioedema, erythema multiforme,        Stevens-Johnson syndrome, atopic keratoconjunctivitis, venereal        keratoconjunctivitis, giant papillary conjunctivitis, and        mastocytosis;    -   inflammatory bowel diseases, including Crohn's disease,        ulcerative colitis, ileitis, enteritis, and necrotizing        enterocolitis;    -   vasculitis, and Behcet's syndrome;    -   psoriasis and inflammatory dermatoses, including dermatitis,        eczema, contact dermatitis, viral cutaneous pathologies        including those derived from human papillomavirus, HIV or RLV        infection, bacterial, flugal, and other parasital cutaneous        pathologies, and cutaneous lupus erythematosus;    -   asthma and respiratory allergic diseases, including allergic        asthma, exercise induced asthma, allergic rhinitis, otitis        media, hypersensitivity lung diseases, chronic obstructive        pulmonary disease and other respiratory problems;    -   autoimmune diseases and inflammatory conditions, including but        are not limited to acute disseminated encephalomyelitis (ADEM).        Addison's disease, antiphospholipid antibody syndrome (APS),        aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's        disease, Diabetes mellitus (type, 1), Goodpasture's syndrome,        Graves' disease. Guillain-Barre syndrome (GBS), Reynaud's        syndrome, Hashimoto's disease, lupus erythematosus, systemic        lupus erythematosus (SLE), multiple sclerosis, myasthenia        gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis,        Ord's thyroiditis, oemphigus, polyarthritis, primary biliary        cirrhosis, psoriasis, rheumatoid arthritis, psoriatic arthritis,        gouty arthritis, spondylitis, reactive arthritis, chronic or        acute glomerulonephritis, lupus nephritis, Reiter's syndrome,        Takayasu's arteritis, temporal arteritis (also known as “giant        cell arteritis”), warm autoimmune hemolytic anemia, Wegener's        granulomatosis, alopecia universalis, Chagas' disease, chronic        fatigue syndrome, dysautonomia, endometriosis, hidradenitis        suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis,        scleroderma, ulcerative colitis, connective tissue disease,        autoimmune pulmonary inflammation, autoimmune thyroiditis,        autoimmune inflammatory eye disease, vitiligo, and vulvodynia.        Other disorders include bone-resorption disorders and        thrombosis;    -   tissue or organ transplant rejection disorders including but not        limited to graft rejection (including allograft rejection and        graft-v-host disease (GVHD)), e.g., skin graft rejection, solid        organ transplant rejection, bone marrow transplant rejection;    -   fever;    -   cardiovascular disorders, including acute heart failure,        hypotension, hypertension, angina pectoris, myocardial        infarction, cardiomyopathy, congestive heart failure,        atherosclerosis, coronary artery disease, restenosis, and        vascular stenosis;    -   cerebrovascular disorders, including traumatic brain injury,        stroke, ischemic reperfusion injury and aneurysm;    -   cancers of the breast, skin, prostate, cervix, uterus, ovary,        testes, bladder, lung, liver, larynx, oral cavity, colon and        gastrointestinal tract (e.g., esophagus, stomach, pancreas),        brain, thyroid, blood, and lymphatic system;    -   fibrosis, connective tissue disease, and sarcoidosis;    -   genital and reproductive conditions, including erectile        dysfunction;    -   gastrointestinal disorders, including gastritis, ulcers, nausea,        pancreatitis, and vomiting;    -   neurologic disorders, including Alzheimer's disease;    -   sleep disorders, including insomnia, narcolepsy, sleep apnea        syndrome, and Pickwick Syndrome;    -   pain, myalgias due to infection;    -   renal disorders;    -   ocular disorders, including glaucoma;    -   infectious diseases, including HIV;    -   sepsis; septic shock; endotoxic shock; gram negative sepsis;        gram positive sepsis; toxic shock syndrome; multiple organ        injury syndrome secondary to septicemia, trauma, or hemorrhage;    -   pulmonary or respiratory conditions including but not limited to        asthma, chronic bronchitis, allergic rhinitis, adult respiratory        distress syndrome (ARDS), severe acute respiratory syndrome        (SARS), chronic pulmonary inflammatory diseases (e.g., chronic        obstructive pulmonary disease), silicosis, pulmonary        sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia,        bronchiectasis, hereditary emphysema, and pulmonary oxygen        toxicity;    -   ischemic-reperfusion injury, e.g., of the myocardium, brain, or        extremities;    -   fibrosis including but not limited to cystic fibrosis; keloid        formation or scar tissue formation;    -   central or peripheral nervous system inflammatory conditions        including but not limited to meningitis (e.g., acute purulent        meningitis), encephalitis, and brain or spinal cord injury due        to minor trauma;    -   Sjorgren's syndrome; diseases involving leukocyte diapedesis;        alcoholic hepatitis; bacterial pneumonia; community acquired        pneumonia (CAP); Pneumocystis carinii pneumonia (PCP);        antigen-antibody complex mediated diseases; hypovolemic shock;        acute and delayed hypersensitivity; disease states due to        leukocyte dyscrasia and metastasis; thermal injury; granulocyte        transfusion associated syndromes; cytokine-induced toxicity;        stroke; pancreatitis; myocardial infarction, respiratory        syncytial virus (RSV) infection; and spinal cord injury.

In certain embodiments, the cancer or cancers treatable with the methodsprovided herein includes, but is or are not limited to,

-   -   leukemias, including, but not limited to, acute leukemia, acute        lymphocytic leukemia, acute myelocytic leukemias such as        myeloblasts, promyelocyte, myelomonocytic, monocytic,        erythroleukemia leukemias and myelodysplastic syndrome or a        symptom thereof (such as anemia, thrombocytopenia, neutropenia,        bicytopenia or pancytopenia), refractory anemia (RA), RA with        ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB        in transformation (RAEB-T), preleukemia, and chronic        myelomonocytic leukemia (CMML);    -   chronic leukemias, including, but not limited to, chronic        myelocytic (granulocytic) leukemia, chronic lymphocytic        leukemia, and hairy cell leukemia;    -   polycythemia vera;    -   lymphomas, including, but not limited to, Hodgkin's disease and        non-Hodgkin's disease;    -   multiple myelomas, including, but not limited to, smoldering        multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma,        plasma cell leukemia, solitary plasmacytoma, and extramedullary        plasmacytoma;    -   Waldenstrom's macroglobulinemia;    -   monoclonal gammopathy of undetermined significance;    -   benign monoclonal gammopathy;    -   heavy chain disease;    -   bone and connective tissue sarcomas, including, but not limited        to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma,        malignant giant cell tumor, fibrosarcoma of bone, chordoma,        periosteal sarcoma, soft-tissue sarcomas, angiosarcoma        (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma,        leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic        cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma;    -   brain tumors, including, but not limited to, glioma,        astrocytoma, brain stem glioma, ependymoma, oligodendroglioma,        nonglial tumor, acoustic neurinoma, craniopharyngioma,        medulloblastoma, meningioma, pineocytoma, pineoblastoma, and        primary brain lymphoma;    -   breast cancer, including, but not limited to, adenocarcinoma,        lobular (small cell) carcinoma, intraductal carcinoma, medullary        breast cancer, mucinous breast cancer, tubular breast cancer,        papillary breast cancer, primary cancers, Paget's disease, and        inflammatory breast cancer;    -   adrenal cancer, including, but not limited to, pheochromocytom        and adrenocortical carcinoma;    -   thyroid cancer, including, but not limited to, papillary or        follicular thyroid cancer, medullary thyroid cancer, and        anaplastic thyroid cancer;    -   pancreatic cancer, including, but not limited to, insulinoma,        gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor,        and carcinoid or islet cell tumor;    -   pituitary cancer, including, but limited to, Cushing's disease,        prolactin-secreting tumor, acromegaly, and diabetes insipidus;    -   eye cancer, including, but not limited, to ocular melanoma such        as iris melanoma, choroidal melanoma, and cilliary body        melanoma, and retinoblastoma;    -   vaginal cancer, including, but not limited to, squamous cell        carcinoma, adenocarcinoma, and melanoma;    -   vulvar cancer, including, but not limited to, squamous cell        carcinoma, melanoma, adenocarcinoma, basal cell carcinoma,        sarcoma, and Paget's disease;    -   cervical cancers, including, but not limited to, squamous cell        carcinoma, and adenocarcinoma;    -   uterine cancer, including, but not limited to, endometrial        carcinoma and uterine sarcoma;    -   ovarian cancer, including, but not limited to, ovarian        epithelial carcinoma, borderline tumor, germ cell tumor, and        stromal tumor;    -   esophageal cancer, including, but not limited to, squamous        cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid        carcinoma, adenosquamous carcinoma, sarcoma, melanoma,        plasmacytoma, verrucous carcinoma, and oat cell (small cell)        carcinoma;    -   stomach cancer, including, but not limited to, adenocarcinoma,        fungating (polypoid), ulcerating, superficial spreading,        diffusely spreading, malignant lymphoma, liposarcoma,        fibrosarcoma, and carcinosarcoma;    -   colon cancer;    -   rectal cancer;    -   liver cancer, including, but not limited to, hepatocellular        carcinoma and hepatoblastoma;    -   gallbladder cancer, including, but not limited to,        adenocarcinoma;    -   cholangiocarcinomas, including, but not limited to, pappillary,        nodular, and diffuse;    -   lung cancer, including, but not limited to, non-small cell lung        cancer, squamous cell carcinoma (epidermoid carcinoma),        adenocarcinoma, large-cell carcinoma, and small-cell lung        cancer;    -   testicular cancer, including, but not limited to, germinal        tumor, seminoma, anaplastic, classic (typical), spermatocytic,        nonseminoma, embryonal carcinoma, teratoma carcinoma, and        choriocarcinoma (yolk-sac tumor);    -   prostate cancer, including, but not limited to, adenocarcinoma,        leiomyosarcoma, and rhabdomyosarcoma;    -   penal cancer;    -   oral cancer, including, but not limited to, squamous cell        carcinoma;    -   basal cancer;    -   salivary gland cancer, including, but not limited to,        adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic        carcinoma;    -   pharynx cancer, including, but not limited to, squamous cell        cancer and verrucous;    -   skin cancer, including, but not limited to, basal cell        carcinoma, squamous cell carcinoma and melanoma, superficial        spreading melanoma, nodular melanoma, lentigo malignant        melanoma, and acral lentiginous melanoma;    -   kidney cancer, including, but not limited to, renal cell cancer,        adenocarcinoma,    -   hypernephroma, fibrosarcoma, and transitional cell cancer (renal        pelvis and/or uterer);    -   Wilms' tumor;    -   bladder cancer, including, but not limited to, transitional cell        carcinoma, squamous cell cancer, adenocarcinoma, and        carcinosarcoma; and other cancer, including, not limited to,        myxosarcoma, osteogenic sarcoma, endotheliosarcoma,        lymphangio-endotheliosarcoma, mesothelioma, synovioma,        hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,        bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland        carcinoma, papillary carcinoma, and papillary adenocarcinomas        See Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co.,        Philadelphia and Murphy et al., 1997, Informed Decisions: The        Complete Book of Cancer Diagnosis, Treatment, and Recovery,        Viking Penguin, Penguin Books U.S.A., Inc., United States of        America.

It will be appreciated that the treatment methods of the invention areuseful in the fields of human medicine and veterinary medicine. Thus,the individual to be treated may be a mammal, preferably human, or otheranimals. For veterinary purposes, individuals include but are notlimited to farm animals including cows, sheep, pigs, horses, and goats;companion animals such as dogs and cats; exotic and/or zoo animals;laboratory animals including mice, rats, rabbits, guinea pigs, andhamsters; and poultry such as chickens, turkeys, ducks, and geese.

In some embodiments, the method of treating inflammatory or autoimmunediseases comprises administering to a subject (e.g. a mammal) atherapeutically effective amount of one or more compounds of the presentinvention that selectively inhibit PI3K-δ and/or PI3K-γ as compared toall other type I PI3 kinases. Such selective inhibition of PI3K-δ and/orPI3K-γ may be advantageous for treating any of the diseases orconditions described herein. For example, selective inhibition of PI3K-δmay inhibit inflammatory responses associated with inflammatorydiseases, autoimmune disease, or diseases related to an undesirableimmune response including but not limited to asthma, emphysema, allergy,dermatitis, rhuematoid arthritis, psoriasis, lupus erythematosus, orgraft versus host disease. Selective inhibition of POK-δ may furtherprovide for a reduction in the inflammatory or undesirable immuneresponse without a concomittant reduction in the ability to reduce abacterial, viral, and/or fungal infection. Selective inhibition of bothPI3K-δ and PI3K-γ may be advantageous for inhibiting the inflammatoryresponse in the subject to a greater degree than that would be providedfor by inhibitors that selectively inhibit PI3K-δ or PI3K-γ alone. Inone aspect, one or more of the subject methods are effective in reducingantigen specific antibody production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more. In another aspect, oneor more of the subject methods are effective in reducing antigenspecific IgG3 and/or IgGM production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more.

In one aspect, one of more of the subject methods are effective inameliorating symptoms associated with rhuematoid arthritis including butnot limited to a reduction in the swelling of joints, a reduction inserum anti-collagen levels, and/or a reduction in joint pathology suchas bone resorption, cartilage damage, pannus, and/or inflammation. Inanother aspect, the subject methods are effective in reducing ankleinflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%,60%, or about 75% to 90%. In another aspect, the subject methods areeffective in reducing knee inflammation by at least about 2%, 5%, 10%,15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more. In stillanother aspect, the subject methods are effective in reducing serumanti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%,25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or more. Inanother aspect, the subject methods are effective in reducing anklehistopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 75%, 80%, 90% or more. In still another aspect, the subject methodsare effective in reducing knee histopathology scores by about 5%, 10%,15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.

In other embodiments, the present invention provides methods of usingthe compounds or pharmaceutical compositions to treat respiratorydiseases including but not limited to diseases affecting the lobes oflung, pleural cavity, bronchial tubes, trachea, upper respiratory tract,or the nerves and muscle for breathing. For example, methods areprovided to treat obstructive pulmonary disease. Chronic obstructivepulmonary disease (COPD) is an umbrella term for a group of respiratorytract diseases that are characterized by airflow obstruction orlimitation. Conditions included in this umbrella term are: chronicbronchitis, emphysema, and bronchiectasis.

In another embodiment, the compounds described herein are used for thetreatment of asthma. Also, the compounds or pharmaceutical compositionsdescribed herein may be used for the treatment of endotoxemia andsepsis. In one embodiment, the compounds or pharmaceutical compositionsdescribed herein are used to for the treatment of rheumatoid arthritis(RA). In yet another embodiment, the compounds or pharmaceuticalcompositions described herein is used for the treatment of contact oratopic dermatitis. Contact dermatitis includes irritant dermatitis,phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis,contact urticaria, systemic contact-type dermatitis and the like.Irritant dermatitis can occur when too much of a substance is used onthe skin of when the skin is sensitive to certain substance. Atopicdermatitis, sometimes called eczema, is a kind of dermatitis, an atopicskin disease.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. In some embodiments, said method relates to thetreatment of cancer such as acute myeloid leukemia, thymus, brain, lung,squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oralcavity and oropharyngeal, bladder, gastric, stomach, pancreatic,bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian,prostate, colorectal, esophageal, testicular, gynecological, thyroid,CNS, PNS, AIDS-related (e.g. Lymphoma and Kaposi's Sarcoma) orviral-induced cancer. In some embodiments, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis), restenosis, or prostate(e.g., benign prostatic hypertrophy (BPH)).

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, ester,prodrug, solvate, hydrate or derivative thereof. In some embodiments,said method is for treating a disease selected from the group consistingof tumor angiogenesis, chronic inflammatory disease such as rheumatoidarthritis, atherosclerosis, inflammatory bowel disease, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

Patients that can be treated with compounds of the present invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative of said compounds, according to the methods of this inventioninclude, for example, patients that have been diagnosed as havingpsoriasis; restenosis; atherosclerosis; BPH; breast cancer such as aductal carcinoma in duct tissue in a mammary gland, medullarycarcinomas, colloid carcinomas, tubular carcinomas, and inflammatorybreast cancer; ovarian cancer, including epithelial ovarian tumors suchas adenocarcinoma in the ovary and an adenocarcinoma that has migratedfrom the ovary into the abdominal cavity; uterine cancer; cervicalcancer such as adenocarcinoma in the cervix epithelial includingsquamous cell carcinoma and adenocarcinomas; prostate cancer, such as aprostate cancer selected from the following: an adenocarcinoma or anadenocarinoma that has migrated to the bone; pancreatic cancer such asepitheliod carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct; bladder cancer such as a transitional cellcarcinoma in urinary bladder, urothelial carcinomas (transitional cellcarcinomas), tumors in the urothelial cells that line the bladder,squamous cell carcinomas, adenocarcinomas, and small cell cancers;leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),and myelodysplastic syndrome (MDS); bone cancer; lung cancer such asnon-small cell lung cancer (NSCLC), which is divided into squamous cellcarcinomas, adenocarcinomas, and large cell undifferentiated carcinomas,and small cell lung cancer; skin cancer such as basal cell carcinoma,melanoma, squamous cell carcinoma and actinic keratosis, which is a skincondition that sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; AIDS-relatedlymphoma such as diffuse large B-cell lymphoma, B-cell immunoblasticlymphoma and small non-cleaved cell lymphoma; Kaposi's Sarcoma;viral-induced cancers including hepatitis B virus (HBV), hepatitis Cvirus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type1 (HTLV-I) and adult T-cell leukemia/lymphoma; and human papilloma virus(HPV) and cervical cancer; central nervous system cancers (CNS) such asprimary brain tumor, which includes gliomas (astrocytoma, anaplasticastrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma,Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheralnervous system (PNS) cancers such as acoustic neuromas and malignantperipheral nerve sheath tumor (MPNST) including neurofibromas andschwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma,malignant meningioma, malignant mesothelioma, and malignant mixedMiillerian tumor; oral cavity and oropharyngeal cancer such as,hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, andoropharyngeal cancer; stomach cancer such as lymphomas, gastric stromaltumors, and carcinoid tumors; testicular cancer such as germ cell tumors(GCTs), which include seminomas and nonseminomas, and gonadal stromaltumors, which include Leydig cell tumors and Sertoli cell tumors; thymuscancer such as to thymomas, thymic carcinomas, Hodgkin disease,non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; andcolon cancer.

The invention also relates to a method of treating diabetes in a mammalthat comprises administering to said mammal a therapeutically effectiveamount of a compound of the present invention, or a pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

In addition, the compounds described herein may be used to treat acne.

In addition, the compounds described herein may be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

Further the compounds described herein may be used for the treatment ofglomerulonephritis. Glomerulonephritis is a primary or secondaryautoimmune renal disease characterized by inflammation of the glomeruli.It may be asymptomatic, or present with hematuria and/or proteinuria.There are many recognized types, divided in acute, subacute or chronicglomerulonephritis. Causes are infectious (bacterial, viral or parasiticpathogens), autoimmune or paraneoplastic.

Additionally, the compounds described herein may be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), addison's disease, antiphospholipid antibody syndrome (APS),aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease,diabetes mellitus (type 1), goodpasture's syndrome, graves' disease,guillain-barre syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonussyndrome (OMS), optic neuritis, ord's thyroiditiSjOstheoarthritis,uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,reiter's syndrome, takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, Wegener's granulomatosis, alopeciauniversalis, chagas¹ disease, chronic fatigue syndrome, dysautonomia,endometriosis, hidradenitis suppurativa, interstitial cystitis,neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo,vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

The invention also relates to a method of treating a cardiovasculardisease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. Examples of cardiovascular conditions include,but are not limited to, atherosclerosis, restenosis, vascular occlusionand carotid obstructive disease.

In another aspect, the present invention provides methods of disruptingthe function of a leukocyte or disrupting a function of an osteoclast.The method includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound of the invention.

In another aspect of the present invention, methods are provided fortreating ophthalmic disease by administering one or more of the subjectcompounds or pharmaceutical compositions to the eye of a subject.

The invention further provides methods of modulating kinase activity bycontacting a kinase with an amount of a compound of the inventionsufficient to modulate the activity of the kinase. Modulate can beinhibiting or activating kinase activity. In some embodiments, theinvention provides methods of inhibiting kinase activity by contacting akinase with an amount of a compound of the invention sufficient toinhibit the activity of the kinase. In some embodiments, the inventionprovides methods of inhibiting kinase activity in a solution bycontacting said solution with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said solution. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in a cell by contacting said cell with an amount of a compoundof the invention sufficient to inhibit the activity of the kinase insaid cell. In some embodiments, the invention provides methods ofinhibiting kinase activity in a tissue by contacting said tissue with anamount of a compound of the invention sufficient to inhibit the activityof the kinase in said tissue. In some embodiments, the inventionprovides methods of inhibiting kinase activity in an organism bycontacting said organism with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said organism. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in an animal by contacting said animal with an amount of acompound of the invention sufficient to inhibit the activity of thekinase in said animal. In some embodiments, the invention providesmethods of inhibiting kinase activity in a mammal by contacting saidmammal with an amount of a compound of the invention sufficient toinhibit the activity of the kinase in said mammal. In some embodiments,the invention provides methods of inhibiting kinase activity in a humanby contacting said human with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said human. In someembodiments, the % of kinase activity after contacting a kinase with acompound of the invention is less than 1, 5, 10, 20, 30, 40, 50, 60, 70,80, 90, 95, or 99% of the kinase activity in the absence of saidcontacting step.

In some embodiments, the kinase is a lipid kinase or a protein kinase.In some embodiments, the kinase is selected from the group consisting ofPI3 kinase including different isorforms such as PI3 kinase α, PI3kinase β, PI3 kinase γ, PI3 kinase δ; DNA-PK; mTor; AbI, VEGFR, Ephrinreceptor B4 (EphB4); TEK receptor tyrosine kinase (HE2); FMS-relatedtyrosine kinase δ (FLT-3); Platelet derived growth factor receptor(PDGFR); RET; ATM; ATR; hSmg-1; Hck; Src; Epidermal growth factorreceptor (EGFR); KIT; Inulsin Receptor (IR) and IGFR.

The invention further provides methods of modulating PI3 kinase activityby contacting a PI3 kinase with an amount of a compound of the inventionsufficient to modulate the activity of the PI3 kinase. Modulate can beinhibiting or activating PI3 kinase activity. In some embodiments, theinvention provides methods of inhibiting PI3 kinase activity bycontacting a PI3 kinase with an amount of a compound of the inventionsufficient to inhibit the activity of the PI3 kinase. In someembodiments, the invention provides methods of inhibiting PI3 kinaseactivity. Such inhibition can take place in solution, in a cellexpressing one or more PI3 kinases, in a tissue comprising a cellexpressing one or more PI3 kinases, or in an organism expressing one ormore PI3 kinases. In some embodiments, the invention provides methods ofinhibiting PI3 kinase activity in an animal (including mammal such ashumans) by contacting said animal with an amount of a compound of theinvention sufficient to inhibit the activity of the PI3 kinase in saidanimal.

The ability of the compounds of the invention to treat arthritis can bedemonstrated in a murine collagen-induced arthritis model [Kakimoto, etal., Cell. Immunol., 142:326-337 (1992)], in a rat collagen-inducedarthritis model [Knoerzer, et al., Toxicol. Pathol., 25:13-[9-(1997)],in a rat adjuvant arthritis model [Halloran, et al., Arthritis Rheum.,39:810-819 (1996)], in a rat streptococcal cell wall-induced arthritismodel [Schimmer, et al., J. Immunol., 160:1466-1477 (1998)], or in aSCID-mouse human rheumatoid arthritis model [Oppenheimer-Marks, et al.,J. Clin. Invest., 101: 1261-1272 (1998)].

The ability of the compounds of the invention to treat Lyme arthritiscan be demonstrated according to the method of Gross, et al., Science,218:703-706, (1998).

The ability of the compounds of the invention to treat asthma can bedemonstrated in a murine allergic asthma model according to the methodof Wegner, et al., Science, 247:456-459 (1990), or in a murinenon-allergic asthma model according to the method of Bloemen, et al, Am.J. Respir. Crit. Care Med., 153:521-529 (1996).

The ability of the compounds of the invention to treat inflammatory lunginjury can be demonstrated in a murine oxygen-induced lung injury modelaccording to the method of Wegner, et al., Lung, 170:267-279 (1992), ina murine immune complex-induced lung injury model according to themethod of Mulligan, et al., J. Immunol., 154:1350-1363 (1995), or in amurine acid-induced lung injury model according to the method of Nagase,et al., Am. J. Respir. Crit. Care Med., 154:504-510 (1996).

The ability of the compounds of the invention to treat inflammatorybowel disease can be demonstrated in a murine chemical-induced colitismodel according to the method of Bennett, et al., J. Pharmacol. Exp.Ther., 280:988-1000 (1997).

The ability of the compounds of the invention to treat autoimmunediabetes can be demonstrated in an NOD mouse model according to themethod of Hasagawa, et al., Int. Immunol., 6:831-838 (1994), or in amurine streptozotocin-induced diabetes model according to the method ofHerrold, et al., Cell Immunol., 157:489-500 (1994).

The ability of the compounds of the invention to treat inflammatoryliver injury can be demonstrated in a murine liver injury modelaccording to the method of Tanaka, et al., J. Immunol., 151:5088-5095(1993).

The ability of the compounds of the invention to treat inflammatoryglomerular injury can be demonstrated in a rat nephrotoxic serumnephritis model according to the method of Kawasaki, et al., J.Immunol., 150: 1074-1083 (1993).

The ability of the compounds of the invention to treat radiation-inducedenteritis can be demonstrated in a rat abdominal irradiation modelaccording to the method of Panes, et al., Gastroenterology,108:1761-1769 (1995).

The ability of the PI3K delta selective inhibitors to treat radiationpneumonitis can be demonstrated in a murine pulmonary irradiation modelaccording to the method of Hallahan, et al., Proc. Natl. Acad. Sci.(USA), 94:6432-6437 (1997).

The ability of the compounds of the invention to treat reperfusioninjury can be demonstrated in the isolated heart according to the methodof Tamiya, et al., Immunopharmacology, 29:53-63 (1995), or in theanesthetized dog according to the model of Hartman, et al., Cardiovasc.Res., 30:47-54 (1995).

The ability of the compounds of the invention to treat pulmonaryreperfusion injury can be demonstrated in a rat lung allograftreperfusion injury model according to the method of DeMeester, et al.,Transplantation, 62:1477-1485 (1996), or in a rabbit pulmonary edemamodel according to the method of Horgan, et al., Am. J. Physiol.,261:H1578-H1584 (1991).

The ability of the compounds of the invention to treat stroke can bedemonstrated in a rabbit cerebral embolism stroke model according to themethod of Bowes, et al., Exp. Neurol., 119:215-219 (1993), in a ratmiddle cerebral artery ischemia-reperfusion model according to themethod of Chopp, et al., Stroke, 25:869-875 (1994), or in a rabbitreversible spinal cord ischemia model according to the method of Clark,et al., Neurosurg., 75:623-627 (1991).

The ability of the compounds of the invention to treat cerebralvasospasm can be demonstrated in a rat experimental vasospasm modelaccording to the method of Oshiro, et al., Stroke, 28:2031-2038 (1997).

The ability of the compounds of the invention to treat peripheral arteryocclusion can be demonstrated in a rat skeletal muscleischemia/reperfusion model according to the method of Gute, et al., Mol.Cell. Biochem., 179:169-187 (1998).

The ability of the compounds of the invention to treat graft rejectioncan be demonstrated in a murine cardiac allograft rejection modelaccording to the method of Isobe, et al., Science, 255:1125-1127 (1992),in a murine thyroid gland kidney capsule model according to the methodof Talento, et al., Transplantation, 55:418-422 (1993), in a cynomolgusmonkey renal allograft model according to the method of Cosimi, et al.,J. Immunol., 144:4604-4612 (1990), in a rat nerve allograft modelaccording to the method of Nakao, et al., Muscle Nerve, 18:93-102(1995), in a murine skin allograft model according to the method ofGorczynski and Wojcik, J. Immunol., 152:2011-2019 (1994), in a murinecorneal allograft model according to the method of He, et al.,Opthalmol. Vis. Sci., 35:3218-3225 (1994), or in a xenogeneic pancreaticislet cell transplantation model according to the method of Zeng, etal., Transplantation, 58:681-689 (1994).

The ability of the compounds of the invention to treat graft-versus-hostdisease (GVHD) can be demonstrated in a murine lethal GVHD modelaccording to the method of Harning, et al., Transplantation, 52:842-845(1991).

The ability of the compounds of the invention to treat cancers can bedemonstrated in a human lymphoma metastasis model (in mice) according tothe method of Aoudjit, et al., J. Immunol., 161:2333-2338 (1998).

Combination Treatment

The present invention also provides methods for combination therapies inwhich an agent known to modulate other pathways, or other components ofthe same pathway, or even overlapping sets of target enzymes are used incombination with a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof. In one aspect, such therapy includes but is notlimited to the combination of the subject compound with chemotherapeuticagents, therapeutic antibodies, and radiation treatment, to provide asynergistic or additive therapeutic effect.

In one aspect, the compounds or pharmaceutical compositions of thepresent invention may present synergistic or additive efficacy whenadministered in combination with agents that inhibit IgE production oractivity. Such combination can reduce the undesired effect of high levelof IgE associated with the use of one or more PI3Kδ inhibitors, if sucheffect occurs. This may be particularly useful in treatment ofautoimmune and inflammatory disorders (AIID) such as rheumatoidarthritis. Additionally, the administration of PI3Kδ or PI3Kδ/γinhibitors of the present invention in combination with inhibitors ofmTOR may also exhibit synergy through enhanced inhibition of the PI3Kpathway.

In a separate but related aspect, the present invention provides acombination treatment of a disease associated with PI3Kδ comprisingadministering a PI3K δ inhibitor and an agent that inhibits IgEproduction or activity. Other exemplary PI3Kδ inhibitors are applicablefor this combination and they are described, e.g., U.S. Pat. No.6,800,620. Such combination treatment is particularly useful fortreating autoimmune and inflammatory diseases (AIID) including but notlimited to rheumatoid arthritis.

Agents that inhibit IgE production are known in the art and they includebut are not limited to one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1/mTORC1 inhibitors,mTORC2/TORC2 inhibitors, and any other compounds that inhibitTORC1/mTORC1 and mTORC2/TORC2. Agents that inhibit IgE activity include,for example, anti-IgE antibodies such as for example Omalizumab andTNX-901.

For treatment of autoimmune diseases, the subject compounds orpharmaceutical compositions can be used in combination with commonlyprescribed drugs including but not limited to Enbrel®, Remicade®,Humira®, Avonex®, and Rebif®. For treatment of respiratory diseases, thesubject compounds or pharmaceutical compositions can be administered incombination with commonly prescribed drugs including but not limited toXolair®, Advair®, Singulair®, and Spiriva®.

The compounds of the invention may be formulated or administered inconjunction with other agents that act to relieve the symptoms ofinflammatory conditions such as encephalomyelitis, asthma, and the otherdiseases described herein. These agents include non-steroidalanti-inflammatory drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen;naproxen; indomethacin; nabumetone; tolmetin; etc. Corticosteroids areused to reduce inflammation and suppress activity of the immune system.The most commonly prescribed drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be veryuseful in some individuals with lupus. They are most often prescribedfor skin and joint symptoms of lupus. Azathioprine (Imuran) andcyclophosphamide (Cytoxan) suppress inflammation and tend to suppressthe immune system. Other agents, e.g. methotrexate and cyclosporin areused to control the symptoms of lupus. Anticoagulants are employed toprevent blood from clotting rapidly. They range from aspirin at very lowdose which prevents platelets from sticking, to heparin/coumadin.

In another one aspect, this invention also relates to a pharmaceuticalcomposition for inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, in combination with an amount of an anti-canceragent (e.g. a chemotherapeutic agent). Many chemotherapeutics arepresently known in the art and can be used in combination with thecompounds of the invention.

In some embodiments, the chemotherapeutic is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec (Imatinib Mesylate), Velcade(bortezomib), Iressa (gefitinib), Sprycel (Dasatinib), and Adriamycin aswell as a host of chemotherapeutic agents. Non-limiting examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclosphosphamide (CYTOXAN™); alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; ethylenimines and methylamelamines includingaltretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, pκ)tfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK.R™₁₃; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol;mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”);cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (TAXOL™,Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel(TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid;esperamicins; capecitabine; and pharmaceutically acceptable salts, acidsor derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide (Casodex), leuprolide, andgoserelin (Zoladex); chlorambucil; gemcitabine; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate;camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO), 17α-Ethinylestradiol,Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,Megestrolacetate, Methylprednisolone, Methyl-testosterone, Prednisolone,Triamcinolone, chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Medroxyprogesteroneacetate, matrix metalloproteinase inhibitors, EGFRinhibitors, Pan Her inhibitors, VEGF inhibitors, including as anti-VEGFantibodies such as Avastin, and small molecules such as ZD6474 andSU6668, vatalanib, BAY-43-9006, SU11248, CP-547632, and CEP-7055.Anti-Her2 antibodies (such as Herceptin from Genentech) may also beutilized. Suitable EGFR inhibitors include gefitinib, erlotinib, andcetuximab. Pan Her inhibitors include canertinib, EKB-569, andGW-572016. Further suitable anticancer agents include, but are notlimited to, Src inhibitors, MEK-1 kinase inhibitors, MAPK kinaseinhibitors, PI3 kinase inhibitors, and PDGF inhibitors, such asimatinib. Also included are anti-angiogenic and antivascular agentswhich, by interrupting blood flow to solid tumors, render cancer cellsquiescent by depriving them of nutrition. Castration which also rendersandrogen dependent carcinomas non-proliferative, may also be utilized.Also included are IGF1R inhibitors, inhibitors of non-receptor andreceptor tyrosine kinases, and inhibitors of integrin signalling.Additional anticancer agents include microtubule-stabilizing agents7-O-methylthiomethylpaclitaxel (disclosed in U.S. Pat. No. 5,646,176),4-desacetyl-4-methylcarbonatepaclitaxel,3′-tert-butyl-3′-N-tert-butyloxycarbonyl-4-desacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel(disclosed in U.S. Ser. No. 09/712,352 filed on Nov. 14, 2000), C-4methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C,epothilone D, desoxyepothilone A, desoxyepothilone B,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7-11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17oxabicyclo [14.1.0]heptadecane-5,9-dione (disclosed in WO 99/02514),[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo[14.1.0]-heptadecane-5,-9-dione (as disclosed in U.S. Pat. No.6,262,094) and derivatives thereof; and microtubule-disruptor agents.Also suitable are CDK inhibitors, an antiproliferative cell cycleinhibitor, epidophyllotoxin; an antineoplastic enzyme; biologicalresponse modifiers; growth inhibitors; antihormonal therapeutic agents;leucovorin; tegafur; and haematopoietic growth factors.

Additional cytotoxic agents include, hexamethyl melamine, idatrexate,L-asparaginase, camptothecin, topotecan, pyridobenzoindole derivatives,interferons, and interleukins. Where desired, the compounds orpharmaceutical composition of the present invention can be used incombination with commonly prescribed anti-cancer drugs such asHerceptin®, Avastin®, Erbitux®, Rituxan®, Taxor, Arimidex®, Taxotere,and Veleade®

This invention further relates to a method for using the compounds orpharmaceutical composition in combination with radiation therapy ininhibiting abnormal cell growth or treating the hyperproliferativedisorder in the mammal Techniques for administering radiation therapyare known in the art, and these techniques can be used in thecombination therapy described herein. The administration of the compoundof the invention in this combination therapy can be determined asdescribed herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At-211,1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as 1-125, 1-131, Yb-169, Ir-192 as a solid source,1-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any 5 solution of radionuclides),e.g., a solution of 1-125 or 1-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation whichcomprises administering to the mammal an amount of a compound of thepresent invention or pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof, which amount is effective issensitizing abnormal cells to treatment with radiation. The amount ofthe compound, salt, or solvate in this method can be determinedaccording to the means for ascertaining effective amounts of suchcompounds described herein.

The compounds or pharmaceutical compositions of the present inventioncan be used in combination with an amount of one or more substancesselected from anti-angiogenesis agents, signal transduction inhibitors,and antiproliferative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-H(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the present invention and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-I. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the present inventionare AG-3340, RO 32-3555, and RS 13-0830.

The invention also relates to a method of and to a pharmaceuticalcomposition of treating a cardiovascular disease in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, or an isotopically-labeled derivative thereof, andan amount of one or more therapeutic agents use for the treatment ofcardiovascular diseases.

Examples for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, antiproliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings comprised by the invention. Moreover, a coating can be used toeffect therapeutic delivery focally within the vessel wall. Byincorporation of the active agent in a swellable polymer, the activeagent will be released upon swelling of the polymer.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, (3-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-Lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a subjectcompound include but are not limited to anti-receptor tyrosine kinaseantibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies(rituximab, tositumomab), and other antibodies such as alemtuzumab,bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

Further therapeutic agents that can be combined with a subject compoundmay be found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the compounds of theinvention will be co-administered with other agents as described above.When used in combination therapy, the compounds described herein may beadministered with the second agent simultaneously or separately. Thisadministration in combination can include simultaneous administration ofthe two agents in the same dosage form, simultaneous administration inseparate dosage forms, and separate administration. That is, a compounddescribed herein and any of the agents described above can be formulatedtogether in the same dosage form and administered simultaneously.Alternatively, a compound of the present invention and any of the agentsdescribed above can be simultaneously administered, wherein both theagents are present in separate formulations. In another alternative, acompound of the present invention can be administered just followed byand any of the agents described above, or vice versa. In the separateadministration protocol, a compound of the present invention and any ofthe agents described above may be administered a few minutes apart, or afew hours apart, or a few days apart.

The methods in accordance with the invention may include administering aPI3-kinase δ selective inhibitor with one or more other agents thateither enhance the activity of the inhibitor or compliment its activityor use in treatment. Such additional factors and/or agents may producean augmented or even synergistic effect when administered with aPI3-kinase δ selective inhibitor, or minimize side effects.

In one embodiment, the methods of the invention may includeadministering formulations comprising a PI3-kinase δ selective inhibitorof the invention with a particular cytokine, lymphokine, otherhematopoietic factor, thrombolytic or anti-thrombotic factor, oranti-inflammatory agent before, during, or after administration of thePI3-kinase δ selective inhibitor. One of ordinary skill can easilydetermine if a particular cytokine, lymphokine, hematopoietic factor,thrombolytic of anti-thrombotic factor, and/or anti-inflammatory agentenhances or compliments the activity or use of the PI3-kinase δselective inhibitors in treatment.

More specifically, and without limitation, the methods of the inventionmay comprise administering a PI3-kinase δ selective inhibitor with oneor more of TNF, IL-1, IL-2, IL-3, IL4, IL-5, IL-6, IL-7, IL-8, IL-9,IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IFN,G-CSF, Meg-CSF, GM-CSF, thrombopoietin, stem cell factor, anderythropoietin. Compositions in accordance with the invention may alsoinclude other known angiopoietins such as Ang-2, Ang4, and Ang-Y, growthfactors such as bone morphogenic protein-1, bone morphogenic protein-2,bone morphogenic protein-3, bone morphogenic protein-4, bone morphogenicprotein-5, bone morphogenic protein-6, bone morphogenic protein-7, bonemorphogenic protein-8, bone morphogenic protein-9, bone morphogenicprotein-10, bone morphogenic protein-11, bone morphogenic protein-12,bone morphogenic protein-13, bone morphogenic protein-14, bonemorphogenic protein-15, bone morphogenic protein receptor IA, bonemorphogenic protein receptor IB, brain derived neurotrophic factor,ciliary neutrophic factor, ciliary neutrophic factor receptor a,cytokine-induced neutrophil chemotactic factor 1, cytokine-inducedneutrophil chemotactic factor 2 alpha, cytokine-induced neutrophilchemotactic factor 2 beta, beta endothelial cell growth factor,endothelin 1, epidermal growth factor, epithelial-derived neutrophilattractant, fibroblast growth factor 4, fibroblast growth factor 5,fibroblast growth factor 6, fibroblast growth factor 7, fibroblastgrowth factor 8, fibroblast growth factor 8b, fibroblast growth factor8c, fibroblast growth factor 9, fibroblast growth factor 10, fibroblastgrowth factor acidic, fibroblast growth factor basic, glial cellline-derived neutrophic factor receptor a1, glial cell line-derivedneutrophic factor receptor a2, growth related protein, growth relatedprotein a, growth related protein .beta., growth related protein.gamma., heparin binding epidermal growth factor, hepatocyte growthfactor, hepatocyte growth factor receptor, insulin-like growth factor I,insulin-like growth factor receptor, insulin-like growth factor II,insulin-like growth factor binding protein, keratinocyte growth factor,leukemia inhibitory factor, leukemia inhibitory factor receptor alpha,nerve growth factor, nerve growth factor receptor, neurotrophin-3,neurptrophin-4, placenta growth factor, placenta growth factor 2,platelet derived endothelial cell growth factor, platelet derived growthfactor, platelet derived growth factor A chain, platelet derived growthfactor AA, platelet derived growth factor AB, platelet derived growthfactor B chain, platelet derived growth factor BB, platelet derivedgrowth factor receptor a, platelet derived growth factor receptor beta,pre-B cell growth stimulating factor, stem cell factor, stem cell factorreceptor, transforming growth factor alpha, transforming growth factorbeta, transforming growth factor beta 1, transforming growth factor beta1.2, transforming growth factor beta 2, transforming growth factor beta3, transforming growth factor beta 5, latent transforming growth factorbeta 1, transforming growth factor beta binding protein I, transforminggrowth factor beta binding protein II, transforming growth factor betabinding protein III, tumor necrosis factor receptor type I, tumornecrosis factor receptor type II, urokinase-type plasminogen activatorreceptor, and chimeric proteins and biologically or immunologicallyactive fragments thereof.

The following general methodology described herein provides the mannerand process of making and using the compound of the present inventionand are illustrative rather than limiting. Further modification ofprovided methodology and additionally new methods may also be devised inorder to achieve and serve the purpose of the invention. Accordingly, itshould be understood that there may be other embodiments which fallwithin the spirit and scope of the invention as defined by thespecification hereto.

Representative compounds of the present invention include thosespecified above in Table 1 and pharmaceutically acceptable saltsthereof. The present invention should not be construed to be limited tothem.

General Method of Preparation of Compounds of the Invention

The compounds of the present invention may be prepared by the followingprocesses. Unless otherwise indicated, the variables (e.g., R, R¹, R²,L₁, Cy¹ and Cy²) when used in the below formulae are to be understood topresent those groups described above in relation to formula (I). Thesemethods can similarly be applied to other compounds of formula IA, IA-I,IA-II, IA-III and/or IA-IV.

Scheme 1: This scheme provides a general process for synthesis of acompound of formula (I) wherein all the variables R, R¹, R², L₁, Cy¹ andCy² are as described above in relation to formula (I)

Compound of formula (1) wherein Ra is Hydrogen or alkyl can be convertedto compound of formula (3) by reacting with a compound of formula (2)wherein LG is a leaving group such as a halogen or an acyl group in thepresence of a lewis acid such as aluminium chloride or borontrifluoride. Compound of formula (3) can be converted to Compound offormula (5) by Kostanecki acylation, i.e., by treating with an anhydrideof formula (4), wherein R¹ and R² is hydrogen or substituted orunsubstituted C₁₋₆ alkyl in the presence of a base. (See Von Kostanecki,S., Rozycki, A., in Ber. 1901, 34, 102 and by Baker, W. in J. Chem.Soc., 1933, 1381). Compound of formula (5) can then be converted to acompound of formula (6) using a suitable halogenating condition that isknown to those skilled in the art. For example, by using bromine in apolar solvent such as acetic acid or N,N-dimethyl formamide or by usinga N-halosuccinimide in the presence of a suitable radical initiator suchas azabis(isobutyronitrile) or benzoyl peroxide. Compounds of formula(6) can then be reacted with a compound of formula Cy²-L₁-H in thepresence of a suitable inorganic base such as potassium carbonate orsodium hydride or an organic base such as triethylamine orN,N-diisopropylethylamine to afford the desired compound of formula (I)wherein R¹ & R² are hydrogen or C₁-C₆ alkyl, Cy¹ is monocyclic orbicyclic substituted or unsubstituted aryl and L₁, R, and Cy² are thesame as described above in relation to formula (I).

Scheme 1A: This scheme provides a general process for synthesis of acompound of formula (I) wherein Cy¹ is

Cy² is

X is CR^(a) or N and all the variables R, R¹, R², L₁, and R^(a) are asdescribed above in relation to formula (I).

By starting with a suitable anisole derivative (1a) and a phenylaceticacid derivative (2a), compounds of formula (6a) can be synthesised asdescribed in scheme 1 for synthesis of compound of formula (6). Compoundof formula (6a) can be reacted with compound of formula (7) wherein X ischosen from CH or N and different occurrence of X can be same ordifferent and Y is chosen from N, CH, C-Hal or C—Ar or C-Het in thepresence of a base to afford the desired compound of formula (I) whereinCy¹ is

Cy² is

X is CR^(a) or N and all the variables R, R¹, R², L₁, and R^(a) are asdescribed above in relation to formula (I).

Using similar methodologies as described above in Scheme 1 & 1A withcertain modifications as known to those skilled in the art can be usedto synthesize compounds of formula IA-I and/or IA-II

wherein the variables are to be understood to present those groupsdescribed above in relation to formula IA-I, IA-II and/or IA-IV usingsuitable intermediates and reagents

For example as illustrated below

Scheme 1B: This scheme provides a method for preparation of compound offormula IA-II wherein R¹ & R² are hydrogen or substituted orunsubstituted C₁₋₆ alkyl, R3 is substituted or unsubstituted aryl orheteroaryl, Cy¹ is monocyclic substituted or unsubstituted aryl and R isthe same as described above in relation to formula (I)

As illustrated in scheme 1B, compound of formula (Ia) wherein Y=C-Hal,i.e., compound of formula (Ib) can be further subjected to a Suzukireaction to give compound of formula (IA-IIa) wherein R³ is substitutedor unsubstituted aryl or heteroaryl. Thus, compound of formula (Ib) canbe reacted with a boronic acid or its ester of formula (8), wherein ringR³ is an substituted or unsubstituted aryl or heteroomatic orheteroaromatic ring, in the presence of a suitable palladium catalystsuch as tetrakis(triphenylphosphine)palladium (0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) in thepresence of a base such as an alkali metal carbonate to afford compoundof formula (IA-IIa). Alternately under Sonogashira reaction conditions,compound of formula (Ib) can be reacted with a compound of formula (9)wherein R^(a) is the same as described above in relation to formula(I)), in the presence of a palladium catalyst, to give compound offormula (IA-IIb) wherein R³ is substituted or unsubstituted alkynyl. TheSuzuki reaction and Sonogashira reaction can be performed under standardthermal conditions or optionally may also be assisted by microwaveirradiation.

Scheme 2: This scheme provides a method for preparation of compound offormula I wherein R¹ & R² are hydrogen or substituted or unsubstitutedC₁₋₆ alkyl, Cy¹ is monocyclic substituted or unsubstituted aryl and L₁,R, and Cy² are the same as described above in relation to formula (I)

Compound of formula (3) can be converted to compound of formula (6b) byreacting with a compound of formula (4b) wherein L₁ is a heteroatomcontaining functional group and PG is a protecting group in the presenceof an ester coupling reagent such as2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate (HATU) or2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate(HBTU). Deprotection of compound of formula (6b) can give a compound offormula (6c). Compound of formula (6c) can then be reacted with acompound of formula Cy²-Lg wherein Lg is a good leaving group such asHalogen in the presence of a suitable base such as potassium carbonateor sodium hydride to provide the desired compounds of formula (I)wherein R¹ & R² are hydrogen or substituted or unsubstituted C₁₋₆ alkyl,Cy¹ is monocyclic substituted or unsubstituted aryl and L₁, R, and Cy²are the same as described above in relation to formula (I)

Scheme 2A: This scheme provides a method for preparation of compound offormula IA-IIIa wherein R¹ & R² are hydrogen or substituted orunsubstituted C₁₋₆ alkyl, Cy¹ is substituted or unsubstituted Phenyl,Cy² is

L₁ is NH and R, n and Cy² are the same as described above in relation toformula (IA-III)

The compound of formula (3a) can be reacted with an N-protected aminoacid of formula (4b1) in the presence of an ester coupling reagent suchas 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate (HATU) or2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate(HBTU) to give compound of formula (6b1). The amine protecting group of(6b1) can be removed to give compound of formula (6c1). Compound offormula (6c1) upon reaction with compound of formula (7a) can givecompound of formula (IA-IIIa) wherein R¹ & R² are hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl, Cy¹ is substituted orunsubstituted Phenyl, Cy² is

L₁ is NH and R, n and Cy² are the same as described above in relation toformula (IA-III). Optionally the coupling of (6c1) with a compound offormula (7a) may be performed in the absence of a base with theassistance of microwave irradiation.

Using similar methodologies as described above in Scheme 2 & 2A withcertain modifications as known to those skilled in the art can be usedto synthesize compounds of formula IA-III.

wherein the variables are to be understood to present those groupsdescribed above in relation to formula IA-III and/or IA-IV usingsuitable intermediates and reagents

For example as illustrated below

Experimental

Unless otherwise mentioned, work-up implies distribution of reactionmixture between the aqueous and organic phases indicated withinparenthesis, separation and drying over Na₂SO₄ of the organic layer andevaporating the solvent to give a residue. RT implies ambienttemperature (25-28° C.).

The terms “solvent,” “organic solvent,” or “inert solvent” each mean asolvent inert under the conditions of the reaction being described inconjunction therewith including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, N-methylpyrrolidone (“NMP”), pyridine and the like. Unlessspecified to the contrary, the solvents used in the reactions describedherein are inert organic solvents. Unless specified to the contrary, foreach gram of the limiting reagent, one cc (or ml) of solvent constitutesa volume equivalent.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation procedurescan be had by reference to the examples herein below. However, otherequivalent separation or isolation procedures can also be used. Unlessotherwise stated, purification implies column chromatography usingsilica gel as the stationary phase and a mixture of petroleum ether(boiling at 60-80° C.) and ethyl acetate or dichloromethane and methanolof suitable polarity as the mobile phases.

When desired, the (R)- and (S)-isomers of the compounds of the presentinvention, if present, may be resolved by methods known to those skilledin the art, for example by formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a specific enantiomer may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer tothe other by asymmetric transformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts.

Many of the optionally substituted starting compounds and otherreactants are commercially available, e.g., from Sigma Aldrich ChemicalCompany, Alfa Aesar( ) or can be readily prepared by those skilled inthe art using commonly employed synthetic methodology. Forinstance—various boronic acids which are used can be obtainedcommercially from various sources.

The compounds of the invention can generally be synthesized by anappropriate combination of generally well known synthetic methods.Techniques useful in synthesizing these chemical entities are bothreadily apparent and accessible to those of skill in the relevant art,based on the instant disclosure.

The compounds of the invention can be synthesized by an appropriatecombination of known synthetic methods in the art. The discussion belowis offered to illustrate certain of the diverse methods available foruse in making the compounds of the invention and is not intended tolimit the scope of reactions or reaction sequences that can be used inpreparing the compounds of the present invention.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

Intermediate 1: 1-(5-Bromo-2-hydroxyphenyl)-2-phenylethanone

Phenylacetic acid (1.09 g, 8.0 mmoles) was dissolved in 5 mldichloromethane. To this mixture, oxalylchloride (1.01 g, 8.0 mmoles)and DMF (3 drops) were added at 0° C. and stirred for 30 min. Thesolvent was evaporated and dissolved in 5 ml dichloromethane. To thismixture, 4-bromoanisole (1 g, 5.34 mmoles) was added and cooled to 0° C.At 0° C. AlCl₃ (1.06 g, 8.0 mmoles) was added and the reaction mixturewas warmed to RT and stirred overnight. The reaction mixture wasquenched by the addition of 2N HCl and extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography to afford the title compound as whitesolid (1 g, 66% yield). MP: 83-86° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ11.56 (s, 1H), 8.01 (d, J=2.2Hz, 1H), 7.64 (dd, J=8.8, 2.5Hz, 1H), 7.32(t, 2H), 7.29 (m,3H), 6.96 (d, J=8.8Hz, 1H), 4.43(s, 2H).

Intermediate 2: 6-Bromo-2-methyl-3-phenyl-4H-chromen-4-one

Intermediate 1 (8.9 g, 30.56 mmoles) was taken in a RB flask and to thisacetic anhydride (59 ml) and sodium acetate (17.5 g, 213 mmoles) wereadded and the mixture was refluxed for 12 h. After cooling to RT, thereaction mixture was quenched by the addition of ice cold water. Thesolid formed was filtered and washed with water. The product was driedunder vacuum to afford the title compound as white solid (9.4 g, 97%yield). MP: 119-121° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.35 (d,J=2.4Hz, 1H), 7.75 (dd, J=11.3, 2.4 Hz, 1H), 7.46 (t, 2H), 7.39 (d,J=7.2Hz, 1H), 7.36 (d, J=8.8Hz, 1H), 7.28(m, 2H), 2.32(s, 3H).

Intermediate 3: 6-Bromo-2-(bromomethyl)-3-phenyl-4H-chromen-4-one

To a solution of Intermediate 2 (4.5 g, 14.27 mmoles) in carbontetrachloride (60 ml) N-bromosuccinimide (2.5 g, 14.27 mmoles) was addedand heated to 80° C. Azobisisobutyronitrile (45 mg) was added to thereaction mixture at 80° C. After 12 h, the reaction mixture was cooledto RT, diluted with dichloromethane and washed with water. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was recrystallised from ethyl acetate:petroleum ether (5:95) to afford the title compound as off white solid(3.3 g, 59% yield). MP: 172-175° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ8.35(d, J=2.4Hz, 1H), 7.80(dd, J=8.8, 2.4 Hz, 1H), 7.50-7.36(m, 6H),4.23(s, 2H).

Intermediate 4: 2-Methyl-3-phenyl-4H-chromen-4-one

To a solution of intermediate 2 (3 g, 9.51 mmoles) in ethanol (30 ml),ammonium formate (6 g, 95.18 mmoles) and palladium on carbon (10%, 300mg) were added and the solution was refluxed for 2 h. The solution wasfiltered through celite, diluted with ethyl acetate, washed with 10%sodium bicarbonate solution (100 ml), dried over sodium sulphate andconcentrated to afford the title compound as off-white solid (1.98 g,86% yield).

¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.17(dd, J=7.9, 1.4 Hz, 1H), 7.61(dt,J=8.5, 1.5 Hz, 1H), 7.38-7.28(m, 5H), 7.25(m, 2H), 2.25(s, 3H).

Intermediate 5: 2-(Bromomethyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 4 (1.9 g, 8.07 mmoles) in carbontetrachloride (30 ml) N-bromosuccinimide (1.43 g, 8.07 mmoles) was addedand heated to 80° C. Azobisisobutyronitrile (20 mg) was added to thereaction mixture at 80° C. After 12 h, the reaction mixture was cooledto RT, diluted with dichloromethane and washed with water. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure to afford the title compound as off white solid (1.62 g, 65%yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.06(d, J=7.6Hz, 1H),7.87(t, J=7.7 Hz, 1H), 7.71(d, J=8.5Hz, 1H), 7.53-7.41(m, 4H), 7.35(d,J=6.8Hz, 2H), 4.37(s, 2H).

Intermediate 6: 1-(5-Bromo-2-hydroxyphenyl)-2-(4-fluorophenyl)ethanone

4-Fluoro phenylacetic acid (12.3 g, 79.79 mmoles) was dissolved in 30 mldichloromethane. To this mixture, oxalylchloride (10.17 g, 79.79 mmoles)and DMF (3 drops) were added at 0° C. and stirred for 30 min. Thesolvent was evaporated and dissolved in 30 ml dichloromethane. To thismixture, 4-bromoanisole (10 g, 53.47 mmoles) was added and cooled to 0°C. At 0° C. AlCl₃ (10.6 g, 79.79 mmoles) was added and the reactionmixture was warmed to RT and stirred overnight. The reaction mixture wasquenched by the addition of 2N HCl and extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as white solid (6.1 g, 37% yield. ¹H-NMR (δppm, CDCl₃, 400 MHz): δ 12.05(s,1H), 7.96(d, J=2.3Hz, 1H), 7.58(dd,J=8.9, 2.4Hz, 1H), 7.24(dt, J=5.4, 1.9Hz, 2H), 7.09(dt, J=8.6, 2.1Hz,2H),6.79(d, J=8.7Hz, 1H), 4.27(s, 2H).

Intermediate 7: 6-Bromo-3-(4-fluorophenyl)-2-methyl-4H-chromen-4-one

Intermediate 6 (6.1 g, 19.73 mmoles) was taken in a RB flask and to thisacetic anhydride (40 ml) and sodium acetate (11.3 g, 137.75 mmoles) wereadded and the mixture was refluxed for 12 h. After cooling to RT, thereaction mixture was quenched by the addition of ice cold water. Thesolid formed was filtered and washed with water. The product was driedunder vacuum to afford the title compound as white solid (4.1 g, 63%yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.35(d, J=1.9Hz, 1H), 7.77(dd,J=8.8, 1.9Hz, 1H), 7.37(d, J=8.9Hz, 1H), 7.27(t, J=5.7Hz, 2H), 7.17(t,J=8.6Hz, 2H), 2.33(s, 3H).

Intermediate 8:6-Bromo-2-(bromomethyl)-3-(4-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 7 (2 g, 6.00 mmoles) in carbontetrachloride (20 ml) N-bromo-succinimide (1.06 g, 5.95 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (20 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the title compound as off white solid (1.20g, 50% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.35(d, J=2.4Hz, 1H),7.81(dd, J=8.9, 2.4 Hz, 1H), 7.43(d, J=8.9Hz, 1H), 7.38(dt, J=5.4, 2.0Hz, 2H), 7.20(t, J=8.6 Hz, 2H), 4.22(s, 2H).

Intermediate 9: 3-(4-Fluorophenyl)-2-methyl-4H-chromen-4-one

To a solution of intermediate 7 (1.5 g, 4.50 mmoles) in ethanol (15 ml),ammonium formate (2.8 g, 45.02 mmole) and palladium on carbon (10%, 15mg) were added and the solution was refluxed for 4 h. The solution wasfiltered through celite, diluted with ethyl acetate, washed with 10%sodium bicarbonate solution (100 ml), dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith ethyl acetate:petroleum ether to afford the title compound as whitesolid (0.8 g, 72% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.71(d,J=7.8 Hz, 1H), 7.69(t, J=7.35 Hz, 1H), 7.47(d, J=8.4 Hz, 1H), 7.42(t,J=7.4 Hz, 1H), 7.29(t, J=9.5 Hz, 2H), 7.16(t, J=8.5 Hz, 2H), 2.33(s,3H).

Intermediate 10: 2-(Bromomethyl)-3-(4-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 9 (0.80 g, 3.146 mmoles) in carbontetrachloride (10 ml) N-bromosuccinimide (0.560 g, 3.146 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (8 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the title compound as off white solid (0.7 g,67% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.23(dd, J=7.9, 1.3Hz,1H), 7.74(dt, J=8.6, 1.5 Hz, 1H), 7.53(d, J=8.3Hz, 1H), 7.45(m, 3H),7.19(t, J=8.7 Hz, 2H), 4.24(s, 2H).

Intermediate 11: 1-(5-bromo-2-hydroxyphenyl)-2-o-tolylethanone

2-Methylphenylacetic acid (9.60 g, 64.15 mmoles) was dissolved in 10 mldichloromethane. To this mixture, oxalylchloride (7 ml, 80.19 mmoles)and DMF (3 drops) were added at 0° C. and stirred for 30 min. Thesolvent was evaporated and dissolved in 100 ml dichloromethane. To thismixture, 4-bromoanisole (10 g, 53.47 mmoles) was added and cooled to 0°C. At 0° C. AlCl₃ (10.6 g, 80.19 mmoles) was added and the reactionmixture was warmed to RT and stirred for 24 h. The reaction mixture wasquenched by the addition of 2N HCl and extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as white solid (5.5 g, 33% yield. ¹H-NMR (δppm, DMSO-_(d6), 400 MHz): δ 11.52(s,1H), 8.02(d, J=2.4Hz, 1H), 7.65(dd,J=8.8, 2.5Hz, 1H), 7.16(m, 4H), 6.97(d, J=8.9Hz, 1H), 4.47(s, 2H),2.14(s, 3H).

Intermediate 12: 6-bromo-2-methyl-3-o-tolyl-4H-chromen-4-one

Intermediate 11 (5.5 g, 16.38 mmoles) was taken in a RB flask and tothis acetic anhydride (50 ml) and sodium acetate (9.40 g, 114.69 mmoles)were added and the mixture was refluxed for 12 h. After cooling to RT,the reaction mixture was quenched by the addition of ice cold water. Thesolid formed was filtered and washed with water. The product was driedunder vacuum to afford the title compound as white solid (1.8 g, 30%yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.35(d, J=1.7Hz, 1H), 7.75(d,J=6.7 Hz, 1H), 7.37(d, J=8.8Hz, 1H), 7.35-7.26(m, 3H), 7.09(d, J=6.9Hz,1H), 2.20(s, 3H).2.15(s, 3H).

Intermediate 13: 6-Bromo-2-(bromomethyl)-3-o-tolyl-4H-chromen-4-one

To a solution of intermediate 12 (0.20 g, 0.607 mmoles) in acetic acid(3 ml) bromine (0.03 ml, 1.21 mmoles) was added at 0° C. The reactionmixture heated to 60° C. After 3 h, the reaction mixture was cooled toRT, quenched by the addition of water. The precipitate formed wasfiltered and dried under reduced pressure to afford the title compoundas off white solid (0.176 g, 71% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 8.35(d, J=2.2Hz, 1H), 7.87(dd, J=8.9, 2.3 Hz, 1H), 7.45(d,J=8.9Hz, 1H), 7.39(m, 3H), 7.17(d, J=7.3 Hz), 7.12(d, J=7.5 Hz)(total1H), 4.20(d, J=10.8Hz), 4.08(d, J=10.7Hz)(total, 2H), 2.17 (s, 3H).

Intermediate 14: 6-Bromo-2-ethyl-3-phenyl-4H-chromen-4-one

Intermediate 1 (2.0 g, 6.86 mmoles) was taken in a RB flask and to thistriethylamine (16 ml) and propionic anhydride (2.80 g, 21.50 mmoles)were added and the mixture was refluxed for 22 h. After cooling to RT,the reaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as off-white solid (0.78 g, 31% yield). ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 8.10(d, J=2.4Hz, 1H), 7.97(dd, J=8.9, 2.4Hz, 1H), 7.68(d, J=8.9Hz, 1H), 7.46(m, 3H), 7.27(d, J=6.9Hz, 2H),2.55(q, J=7.5Hz, 2H), 1.19(t, J=7.5Hz, 3H).

Intermediate 15: 6-Bromo-2-(1-bromoethyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 14 (1.0 g, 3.03 mmoles) in carbontetrachloride (25 ml) N-bromosuccinimide (0.540 g, 3.03 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (5 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the title compound as off white solid (0.6 g,50% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.11(d, J=2.5Hz, 1H),8.04(dd, J=8.9,2.5 Hz, 1H), 7.78(d, J=9.0Hz, 1H), 7.51(m, 3H), 7.32(dd,J=8.1, 1.7 Hz, 2H), 4.97(q, J=6.8Hz, 1H),1.96(d, J=6.8Hz, 3H).

Intermediate 16: (S)-tert-butyl1-(6-bromo-4-oxo-3-phenyl-4H-chromen-2-yl)-ethylcarbamate

To a solution of intermediate 1 (5 g, 17.17 mmoles) in dichloromethane(50 ml), triethylamine (5.2 g, 51.52 mmoles) was added followed byL-N-Boc-Alanine (3.5 g, 18.89 mmoles). To this mixture HATU (13 g, 34.34mmoles) was added and stirred at RT for 12 h. The reaction mixture wasquenched by the addition of water and extracted with dichloromethane.The organic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with ethyl acetate: petroleum ether to afford the titlecompound as yellow solid (1.6 g, 21% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 8.10(d, J=2.4Hz, 1H), 7.99(dd, J=8.9,2.5 Hz, 1H), 7.62 (d, J=8.9Hz, 1H), 7.53(d, J=6.8 Hz, 1H), 7.47 (m, 3H), 7.29(d, J=7.0 Hz, 2H),4.49(q, J=6.9Hz, 1H),1.33(s, 9H), 1.29(d, J=7.1Hz, 3H).

Intermediate 17: (S)-2-(1-aminoethyl)-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of intermediate 16 (0.81 g, 1.821 mmoles) indichloromethane (10 ml), trifluoroacetic acid (1.4 ml, 18.21 mmoles) wasadded and stirred at RT for 2 h. The reaction mixture was concentrated,basified with sodium bicarbonate solution, extracted with ethyl acetate.The organic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as yellow solid(0.675 g). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.10(d, J=2.4Hz, 1H),8.00(dd, J=8.9,2.5 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.46 (m, 4H),7.30(d, J=7.0 Hz, 2H), 7.28 (m,1H), 3.78(q, J=6.7Hz, 1H), 1.29(d,J=6.7Hz, 3H).

Intermediate 18:tert-Butyl(6-bromo-4-oxo-3-phenyl-4H-chromen-2-yl)methylcarbamate

To a solution of intermediate 1 (2 g, 6.86 mmoles) in dichloromethane(20 ml), triethylamine (2.08 g, 51.52 mmoles) was added followed byN-Boc-Glycine (1.3 g, 7.55 mmoles). To this mixture HATU (5.2 g, 13.67mmoles) was added and stirred at RT for 12 h. The reaction mixture wasquenched by the addition of water and extracted with dichloromethane.The organic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with ethyl acetate: petroleum ether to afford the titlecompound as yellow solid (1.0 g, 33% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 8.12(d, J=2.3Hz, 1H), 7.99(dd, J=8.9,2.5 Hz, 1H), 7.59 (d, J=8.9Hz, 1H), 7.476(m, 4H), 7.31(d, J=6.3 Hz, 2H), 4.06(d, J=5.6Hz,2H),1.37(s, 9H).

Intermediate 19: 2-(Amino methyl)-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of intermediate 18 (0.440 g, 1.02 mmoles) indichloromethane (5 ml), trifluoroacetic acid (3 ml) was added andstirred at RT for 2 h. The reaction mixture was concentrated, basifiedwith sodium bicarbonate solution, extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as brown liquid(0.400 g). The crude product was taken for next step.

Intermediate 20:1-(2-Hydroxy-5-methoxyphenyl)-2-phenylethanone

Phenylacetic acid (7.39 g, 54.28 mmoles) was dissolved in 50 mldichloromethane. To this mixture, oxalylchloride (4.74 ml, 54.28 mmoles)and DMF (3 drops) were added at 0° C. and stirred for 30 min. Thesolvent was evaporated and dissolved in 30 ml dichloromethane. To thismixture, 4-methoxyanisole (10 g, 53.47 mmoles) was added and cooled to0° C. At 0° C. AlCl₃ (9.63 g, 72.37 mmoles) was added and the reactionmixture was warmed to RT and stirred for 12 h. The reaction mixture wasquenched by the addition of 2N HCl and extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as yellow liquid (4.3 g, 49% yield. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 11.30(s,1H), 7.42(d, J=3.0Hz, 1H),7.33-7.21(m, 5H), 7.17(dd, J=9.0,3.1Hz, 1H), 6.92(d, J=9.0 Hz, 1H),4.43(s, 2H), 3.74(s, 3H).

Intermediate 21: 6-Methoxy-2-methyl-3-phenyl-4H-chromen-4-one

Intermediate 20 (4 g, 16.51 mmoles) was taken in a RB flask and to thisacetic anhydride (40 ml) and sodium acetate (9.48 g, 115.57 mmoles) wereadded and the mixture was refluxed for 12 h. After cooling to RT, thereaction mixture was quenched by the addition of ice cold water. Thesolid formed was filtered and washed with water. The product was driedunder vacuum to afford the title compound as yellow solid (3 g, 68%yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 7.60(d, J=3.0 Hz, 1H), 7.45(t,J=7.1Hz, 2H), 7.37(m, 2H), 7.29(m, 3H), 3.89(s, 3H).2.31(s, 3H).

Intermediate 22: 2-(Bromomethyl)-6-methoxy-3-phenyl-4H-chromen-4-one

To a solution of intermediate 21 (2.0 g, 7.501 mmoles) in carbontetrachloride (25 ml) N-bromosuccinimide (1.30 g, 7.510 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (25 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off white solid(2.6 g). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 7.68(d, J=9.1 Hz, 1H),7.53(m, 5H), 7.34(d, J=6.7, 2H), 4.36(s, 2H),3.85(s, 3H).

Intermediate 23: 1-(5-Bromo-2-hydroxyphenyl)-2-(2-fluorophenyl)ethanone

2-Fluorophenylacetic acid (2.96 g, 19.24 mmoles) was dissolved in 50 mldichloromethane. To this mixture, oxalylchloride (2.1 ml, 24.05 mmoles)and DMF (3 drops) were added at 0° C. and stirred for 30 min. Thesolvent was evaporated and dissolved in 30 ml dichloromethane. To thismixture, 4-bromoanisole (3.0 g, 16.03 mmoles) was added and cooled to 0°C. At 0° C. AlCl₃ (3.21 g, 24.05 mmoles) was added and the reactionmixture was warmed to RT and stirred for 12 h. The reaction mixture wasquenched by the addition of 2N HCl and extracted with ethyl acetate,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as off-white solid (4.0 g, 81% yield. ¹H-NMR(δ ppm, CDCl₃, 400 MHz): δ 11.97(s,1H), 8.01(d, J=1.7Hz, 1H), 7.58(dd,J=8.8,2.3.1Hz, 1H), 7.35(m,1H), 7.23(d, J=7.3 Hz, 1H), 7.17(m, 2H),6.92(d, J=8.9 Hz, 1H),4.33(s, 2H).

Intermediate 24: 6-Bromo-2-ethyl-3-(2-fluorophenyl)-4H-chromen-4-one

Intermediate 23 (1.1 g, 3.55 mmoles) was taken in a RB flask and to thistriethylamine (10 ml) and propionic anhydride (1.44 g, 11.13 mmoles)were added and the mixture was refluxed for 22 h. After cooling to RT,the reaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as off-white solid (0.800 g, 65% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.10(d, J=2.5Hz, 1H), 8.00(dd,J=9.0,2.5 Hz, 1H), 7.71(d, J=9.0Hz, 1H), 7.51(m, 1H), 7.36(m, 3H),2.54(m, 2H), 1.19(t, J=7.6Hz, 3H).

Intermediate 25:6-Bromo-2-(1-bromoethyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 24 (0.620 g, 1.785 mmoles) in carbontetrachloride (10 ml) N-bromosuccinimide (0.317 g, 1.785 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (15 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off white solidconsisting of two atrop-isomers (0.625 g). ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 8.13(t, J=2.3 Hz, 1H), [8.07(dd, J=2.4,1.0Hz), 8.04(dd,J=2.5,1.1Hz), 1H], 7.81(dd, J=8.8,1.6 Hz, 1H), 7.57(m, 1H), 7.39(m,3H),[4.99(q, J=6.8Hz), 4.93(q, J=6.8Hz), 1H], [1.99(q, J=6.8Hz), 1.44(q,J=6.8Hz), 3H].

Intermediate 26: 6-Bromo-3-(2-fluorophenyl)-2-methyl-4H-chromen-4-one

Intermediate 23 (5 g, 16.17 mmoles) was taken in a RB flask and to thisacetic anhydride (40 ml) and sodium acetate (9.2 g, 82.03 mmoles) wereadded and the mixture was refluxed for 12 h. After cooling to RT, thereaction mixture was quenched by the addition of ice cold water. Thesolid formed was filtered and washed with water. The product was driedunder vacuum to afford the title compound as off-white solid (3.81 g,71% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.34(d, J=2.3Hz, 1H),7.76(dd, J=8.8, 2.2Hz, 1H), 7.41(m, 2H), 7.24(m, 2H), 7.18(t, J=8.9Hz,1H), 2.30(s, 3H).

Intermediate 27:6-Bromo-2-(bromomethyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 26 (2.0 g, 6.00 mmoles) in carbontetrachloride (20 ml) N-bromosuccinimide (1.0 g, 6.00 mmoles) was addedand heated to 80° C. Azobisisobutyronitrile (25 mg) was added to thereaction mixture at 80° C. After 12 h, the reaction mixture was cooledto RT, diluted with dichloromethane and washed with water. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure to afford the crude title compound as off white solid (1.86 g).¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.34(d, J=2.3 Hz, 1H), 7.82(dd,J=8.9,2.3 Hz, 1H), 7.44(d, J=8.8Hz, 1H), 7.38(t, J=6.2Hz, 1H), 7.29(m,2H), [4.22(d, J=11.0 Hz), 4.17(d, J=11.1 Hz), 2H].

Intermediate 28: 2-Ethyl-3-phenyl-4H-chromen-4-one

To a solution of intermediate 24 (1.0 g, 3.03 mmoles) in ethanol (10ml), ammonium formate (1.9 g, 30.14 mmoles) and palladium on carbon(10%, 100 mg) were added and the solution was refluxed for 4 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated. The crude product was purified by columnchromatography with ethyl acetate:petroleum ether to afford the titlecompound as white solid (0.50 g, 66% yield). ¹H-NMR (δ ppm, CDCl₃, 400MHz): δ 8.24(dd, J=7.9,1.4 Hz, 1H), 7.68(dt, J=8.6, 1.6 Hz, 1H),7.48-7.35(m, 5H), 7.28(dd, J=8.3, 1.4 Hz, 2H), 2.62(q, J=7.5 Hz, 2H),1.28(t, J=7.5 Hz, 3H).

Intermediate 29: 2-(1-Bromoethyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 28 (0.550 g, 2.20 mmoles) in carbontetrachloride (10 ml) N-bromosuccinimide (0.392 g, 2.20 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (5 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as yellow solid(0.680 g, 94% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.24(dd,J=8.0,1.7 Hz, 1H), 7.74(dt, J=7.2,1.6Hz, 1H), 7.57(d, J=8.0 Hz, 1H),7.49-7.26(m, 6H), 4.99(q, J=6.9Hz, 1H),1.99(d, J=6.9Hz, 3H).

Intermediate 30: 6-Bromo-3-phenyl-2-propyl-4H-chromen-4-one

Intermediate 1 (3.0 g, 10.30 mmoles) was taken in a RB flask and to thistriethylamine (30 ml) and butyric anhydride (5.12 g, 32.37 mmoles) wereadded and the mixture was refluxed for 22 h. After cooling to RT, thereaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as off-white solid (2.0 g, 56% yield). ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 8.10(d, J=2.4Hz, 1H), 7.97(dd, J=8.9,2.5Hz, 1H), 7.68(d, J=8.9Hz, 1H), 7.46(m, 3H), 7.26(dd, J=8.2,1.3 Hz, 2H),2.49(t, J=1.6Hz, 2H), 1.66(m, 2H), 0.84(t, J=7.4Hz, 3H).

Intermediate 31: 3-Phenyl-2-propyl-4H-chromen-4-one

To a solution of intermediate 30 (1.5 g, 4.37 mmoles) in ethanol (15ml), ammonium formate (2.7 g, 43.70 mmoles) and palladium on carbon(10%, 100 mg) were added and the solution was refluxed for 2 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated. The crude product was purified by columnchromatography with ethyl acetate:petroleum ether to afford the titlecompound as white solid (0.43 g, % yield). ¹H-NMR (δ ppm, CDCl₃, 400MHz): δ 8.24(dd, J=7.9,1.5 Hz, 1H), 7.68(dt, J=7.2,1.6 Hz, 1H),7.46-7.35(m, 5H), 7.27(dd, J=7.2, 1.5 Hz, 2H), 2.57(t, J=7.6 Hz, 2H),1.78(m, 2H0, 0.93(t, J=7.4 Hz, 3H).

Intermediate 32: 2-(1-Bromopropyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 31 (0.900 g, 3.40 mmoles) in carbontetrachloride (15 ml) N-bromosuccinimide (0.606 g, 3.40 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (9 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the title compound as yellow solid (0.880 g,75% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.24(dd, J=8.0,1.6 Hz,1H), 7.74(dt, J=7.2,1.7Hz, 1H), 7.55(d, J=8.3Hz, 1H), 7.49-7.20(m, 6H),4.71(t, J=7.6Hz, 1H),2.33(m, 2H), 0.97(d, J=7.4Hz, 3H).

Intermediate 33: 1-(5-Bromo-2-hydroxyphenyl)-2-(3-fluorophenyl)ethanone

3-Fluorophenylacetic acid (4.90 g, 32.07 mmoles) was dissolved in 50 mldichloromethane. To this mixture, oxalylchloride (3.5 ml, 40.08 mmoles)and DMF (3 drops) were added at 0° C. and stirred for 30 min. Thesolvent was evaporated and dissolved in 50 ml dichloromethane. To thismixture, 4-bromoanisole (5.0 g, 26.72 mmoles) was added and cooled to 0°C. At 0° C. AlCl₃ (5.3 g, 40.08 mmoles) was added and the reactionmixture was warmed to RT and stirred for 12 h. The reaction mixture wasquenched by the addition of 2N HCl, extracted with ethyl acetate, driedover sodium sulphate and concentrated. The crude product was purified bycolumn chromatography with ethyl acetate:petroleum ether to afford thetitle compound as off-white solid (6.6 g, 80% yield. ¹H-NMR (δ ppm,CDCl₃, 400 MHz): δ 12.02(s,1H), 7.94(d, J=2.4Hz, 1H), 7.57(dd,J=8.9,2.4.1Hz, 1H), 7.36(m,1H), 7.04(m, 3H), 6.90(d, J=8.9 Hz,1H),4.28(s, 2H).

Intermediate 34: 6-Bromo-2-ethyl-3-(3-fluorophenyl)-4H-chromen-4-one

Intermediate 33 (3.0 g, 9.70 mmoles) was taken in a RB flask and to thistriethylamine (30 ml) and propionic anhydride (3.94 g, 30.37 mmoles)were added and the mixture was refluxed for 24 h. After cooling to RT,the reaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as off-white solid (1.30 g, 39% yield). ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 8.10(d, J=2.3Hz, 1H), 7.99(dd, J=8.9,2.4Hz, 1H), 7.69(d, J=8.9Hz, 1H), 7.51(q, J=7.9Hz, 1H), 7.25(dt, J=10.8,2.4Hz, 1H), 7.15(t, J=12.2 Hz, 2H), 2.57(q, J=7.6Hz, 2H), 1.20(t, J=7.5Hz,3H).

Intermediate 35: 2-Ethyl-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 34 (1.0 g, 2.88 mmoles) in ethanol (10ml), ammonium formate (1.81 g, 28.80 mmoles) and palladium on carbon(10%, 80 mg) were added and the solution was refluxed for 2 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated to afford the crude title compound ascolourless oil (0.792 g). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.05(dd,J=7.9,1.3 Hz, 1H), 7.83(dt, J=8.6, 1.6 Hz, 1H), 7.67(d, J=8.3 Hz, 1H),7.50(m, 2H), 7.24(dt, J=8.8, 2.5 Hz, 1H), 7.15(t, J=12.3 Hz, 2H),2.55(q, J=7.6 Hz, 2H), 1.20(t, J=7.6 Hz, 3H).

Intermediate 36: 2-(1-Bromoethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 35 (0.700 g, 2.60 mmoles) in carbontetrachloride (10 ml) N-bromosuccinimide (0.464 g, 2.60 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (10 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off-white solid(0.820 g, 91% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.06(dd,J=7.9,1.1 Hz, 1H), 7.89(dt, J=8.4,1.3Hz, 1H), 7.77(d, J=8.3Hz, 1H),7.56(d, J=7.5Hz, 1H), 7.52(d, J=7.7Hz, 1H), 7.31(dt, J=8.6,2.1Hz, 1H),7.19(t, J=9.0Hz, 2H), 5.02(q, J=6.8Hz, 1H),1.97(d, J=6.8Hz, 3H).

Intermediate 37: 3-(2-Fluorophenyl)-2-methyl-4H-chromen-4-one

To a solution of intermediate 26 (0.5 g, 1.50 mmoles) in ethanol (5 ml),ammonium formate (0.945 g, 15.0 mmoles) and palladium on carbon (10%, 40mg) were added and the solution was refluxed for 2 h. The solution wasfiltered through celite, diluted with ethyl acetate, washed with 10%sodium bicarbonate solution (100 ml), dried over sodium sulphate andconcentrated to afford the title compound as white solid (0.302 g, 79%yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.05(dd, J=7.9, 1.5 Hz, 1H),7.84(m,1H), 7.67(d, J=8.3 Hz, 1H), 7.51(m, 2H), 7.37(dt, J=7.3, 1.7 Hz,1H), 7.29(m,2H), 2.26(s, 3H).

Intermediate 38: 2-(Bromomethyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 37 (0.300 g, 1.17 mmoles) in carbontetrachloride (10 ml) N-bromosuccinimide (0.210 g, 1.17 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (15 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off-white solid(0.281 g, 71% yield).

Intermediate 39: 2-Ethyl-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 24 (0.770 g, 2.21 mmoles) in ethanol (10ml), ammonium formate (1.39 g, 22.18 mmoles) and palladium on carbon(10%, 60 mg) were added and the solution was refluxed for 2 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated to afford the title compound as white solid(0.560 g, 94% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.05(dd, J=7.9,1.5 Hz, 1H), 7.85(dt, J=7.3,1.7 Hz, 1H), 7.69(d, J=8.3Hz, 1H),7.52(m,2H), 7.36(m, 2H), 2.52(m, 2H),1.19(t, J=7.5Hz,3H).

Intermediate 40: 2-(1-Bromoethyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 39 (0.600 g, 2.27 mmoles) in carbontetrachloride (10 ml) N-bromosuccinimide (0.404 g, 2.27 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (15 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off-white solid(0.420 g, 53% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.07(dd,J=7.9,1.3 Hz, 1H), 7.92(dt, J=8.4,1.3Hz, 1H), 7.79(d, J=8.4Hz, 1H),7.56(m, 2H), 7.41(m, 3H), [4.99(q, J=6.8Hz), 4.93(q, J=6.7Hz), 1H],[2.00(d, J=6.8Hz), 1.95(d, J=6.Hz), 3H].

Intermediate 41: 6-Bromo-3-(2-fluorophenyl)-2-propyl-4H-chromen-4-one

Intermediate 23 (2.0 g, 6.46 mmoles) was taken in a RB flask and to thistriethylamine (20 ml) and butyric anhydride (3.19 g, 20.25 mmoles) wereadded and the mixture was refluxed for 24 h. After cooling to RT, thereaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as colourless liquid (1.60 g, 69% yield).

Intermediate 42: 3-(2-Fluorophenyl)-2-propyl-4H-chromen-4-one

To a solution of intermediate 41 (1.60 g, 4.43 mmoles) in ethanol (15ml), ammonium formate (2.79 g, 63.03 mmoles) and palladium on carbon(10%, 130 mg) were added and the solution was refluxed for 2 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated to afford the title compound as brown liquid(1.0 g, 81% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.05 (dd, J=7.9,1.4 Hz, 1H), 7.84(dt, J=8.5,1.5 Hz, 1H), 7.68(d, J=8.4Hz, 1H), 7.51(q,J=7.7Hz, 2H), 7.34(m, 3H), 2.49(m, 2H),1.68(q, J=7.4Hz,2H), 1.17(t,J=7.4Hz,3H)

Intermediate 43: 2-(1-Bromopropyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 42 (1.00 g, 3.59 mmoles) in carbontetrachloride (20 ml) N-bromosuccinimide (0.639 g, 3.59 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (15 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off-white solid(0.700 g, 54% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.07(d,J=7.9Hz, 1H), 7.91(t, J=7.9Hz, 1H), 7.78(dd, J=8.3,2.0Hz, 1H), 7.56(t,J=7.6Hz, 2H), 7.36(m, 3H), [4.69(t, J=7.6Hz), 4.64(t, J=7.5Hz), 1H],2.38(m,2H), [0.97(t, J=7.3Hz), 0.88(t, J=7.2Hz), 3H].

Intermediate 44: 6-Bromo-3-(3-fluorophenyl)-2-propyl-4H-chromen-4-one

Intermediate 33 (3.0 g, 9.70 mmoles) was taken in a RB flask and to thistriethylamine (3 ml) and butyric anhydride (4.55 g, 30.37 mmoles) wereadded and the mixture was refluxed for 24 h. After cooling to RT, thereaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as colourless liquid (0.794 g, 23% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.10(d, J=2.5Hz, 1H), 7.98(dd,J=8.9,2.5 Hz, 1H), 7.69(d, J=8.9Hz, 1H), 7.51(q, J=8.0Hz, 1H), 7.26(dt,J=8.7, 2.5 Hz, 1H), 7.14(dt, J=9.9,2.3 Hz, 2H), 2.55(m,2H), 1.68(q,J=7.5Hz, 2H), 0.85(t, J=7.5Hz, 3H).

Intermediate 45: 3-(3-Fluorophenyl)-2-propyl-4H-chromen-4-one

To a solution of intermediate 44 (0.750 g, 2.07 mmoles) in ethanol (10ml), ammonium formate (1.30 g, 20.76 mmoles) and palladium on carbon(10%, 80 mg) were added and the solution was refluxed for 2 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated to afford the title compound as colourlessliquid (0.51 g, 87% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.05(dd,J=8.0,1.3 Hz, 1H), 7.83(dt, J=8.4,1.3 Hz, 1H), 7.66(d, J=8.4Hz, 1H),7.51(m, 2H), 7.24(dt, J=8.9,2.5Hz, 1H), 7.14(t, J=8.1Hz, 2H), 2.53(m,2H), 1.69(m, 2H),0.85 (t, J=7.3Hz,3H).

Intermediate 46: 2-(1-Bromopropyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 45 (0.48 g, 1.70 mmoles) in carbontetrachloride (10 ml) N-bromosuccinimide (0.302 g, 1.70 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (10 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off-white solid(0.540 g, 88% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.07(dd,J=7.9,1.5Hz, 1H), 7.89(dt, J=8.5,1.5Hz, 1H), 7.75(d, J=8.4Hz, 1H),7.57(q, J=8.0Hz, 2H), 7.32(dt, J=8.6,2.5Hz, 1H),7.17(dt,J=8.4,2.3Hz,2H), 4.70(t, J=7.5Hz, 1H), 2.34(m,1H), 2.20(m,1H), 0.92(t,J=7.2Hz,3H).

Intermediate 47: 6-Bromo-3-(4-fluorophenyl)-2-propyl-4H-chromen-4-one

Intermediate 6 (3.0 g, 9.70 mmoles) was taken in a RB flask and to thistriethylamine (30 ml) and butyric anhydride (4.55 g, 30.37 mmoles) wereadded and the mixture was refluxed for 24 h. After cooling to RT, thereaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as colourless liquid (2.55 g, 71% yield).¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.33(d, J=2.3Hz, 1H), 7.76(dd,J=8.8,2.3 Hz, 1H), 7.36(d, J=8.9Hz, 1H), 7.23(dd, J=8.7,5.6Hz, 2H),7.15(t, J=8.7Hz, 2H), 2.55(t, J=7.5Hz, 2H), 1.77(m, 2H), 0.93(t,J=7.4Hz, 3H).

Intermediate 48: 3-(4-Fluorophenyl)-2-propyl-4H-chromen-4-one

To a solution of intermediate 47 (1.00 g, 2.76 mmoles) in ethanol (10ml), ammonium formate (1.70 g, 27.60 mmoles) and palladium on carbon(10%, 80 mg) were added and the solution was refluxed for 1 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated to afford the title compound as colourlessliquid (0.750 g, 96% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.23(dd,J=7.9,1.4 Hz, 1H), 7.69(dt, J=8.5,1.5 Hz, 1H), 7.47(d, J=8.4Hz, 1H),7.41(t, J=7.8Hz, 1H), 7.25(m, 2H), 7.15(t, J=8.7Hz, 2H), 2.56(t,J=7.5Hz, 2H), 1.78(m, 2H),0.94 (t, J=7.3Hz,3H).

Intermediate 49: 2-(1-Bromopropyl)-3-(4-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 48 (0.700 g, 2.47 mmoles) in carbontetrachloride (10 ml) N-bromosuccinimide (0.441 g, 2.47 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile 7 mg) was added to thereaction mixture at 80° C. After 12 h, the reaction mixture was cooledto RT, diluted with dichloromethane and washed with water. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure to afford the crude title compound as off-white solid (1.1 g).¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.23(dd, J=8.0,1.2Hz, 1H), 7.74(dt,J=8.4,1.3Hz, 1H), 7.55(d, J=8.4Hz, 1H), 7.45(t, J=7.4Hz, 1H), 7.35(m,2H),7.19(t, J=8.7Hz,2H), 4.68(t, J=7.7Hz, 1H), 2.31(m,2H), 0.97(t,J=7.3Hz,3H).

Intermediate 50:1-(5-Fluoro-2-hydroxyphenyl)-2-phenylethanone

Phenylacetic acid (8.09 g, 59.46 mmoles) was dissolved in 15 mldichloromethane. To this mixture, oxalylchloride (5.2 ml, 59.46 mmoles)and DMF (3 drops) were added at 0° C. and stirred for 30 min. Thesolvent was evaporated and dissolved in 15 ml dichloromethane. To thismixture, 4-fluoroanisole (5.0 g, 39.64 mmoles) was added and cooled to0° C. At 0° C. AlCl₃ (7.92 g, 59.46 mmoles) was added and the reactionmixture was warmed to RT and stirred for 12 h. The reaction mixture wasquenched by the addition of 2N HCl, extracted with ethyl acetate, driedover sodium sulphate and concentrated. The crude product was purified bycolumn chromatography with ethyl acetate:petroleum ether to afford thetitle compound as off-white solid (5.1 g, 56% yield. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): δ 11.43(s,1H), 7.77(dd, J=9.5,3.2Hz, 1H), 7.42(dt,J=8.7,3.2Hz, 1H), 7.33(t, J=7.3Hz, 2H), 7.26(m, 3H), 7.01(q, J=4.6 Hz,1H),4.42(s, 2H).

Intermediate 51: 6-Fluoro-3-phenyl-2-propyl-4H-chromen-4-one

Intermediate 50 (1.6 g, 6.94 mmoles) was taken in a RB flask and to thistriethylamine (16 ml) and butyric anhydride (3.43 g, 21.72 mmoles) wereadded and the mixture was refluxed for 24 h. After cooling to RT, thereaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as colourless liquid (1.40 g, 71% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.79(dd, J=10.2, 4.3Hz, 1H),7.73(dt, J=6.4,3.1 Hz, 2H), 7.46(t, J=6.9Hz, 2H), 7.42(m, 1H), 7.26(dd,J=8.3,1.5Hz, 2H), 2.52(t, J=7.4Hz, 2H), 1.70(m, 2H), 0.84(t, J=7.4Hz,3H).

Intermediate 52: 2-(1-Bromopropyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of intermediate 51 (1.30 g, 4.60 mmoles) in carbontetrachloride (20 ml) N-bromosuccinimide (0.818 g, 4.60 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (10 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off-white solid(1.40 g, 84% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.88(dd,J=9.2,4.3Hz, 1H), 7.80-7.71(m, 2H), 7.52-7.42(m, 3H), 7.29(d, J=6.8Hz,2H), 4.68(t, J=7.6Hz, 1H), 2.34-2.15(m,2H), 0.91(t, J=7.3Hz,3H).

Intermediate 53: 6-Bromo-2-ethyl-3-(4-fluorophenyl)-4H-chromen-4-one

Intermediate 6 (3.0 g, 9.70 mmoles) was taken in a RB flask and to thistriethylamine (30 ml) and propionic anhydride (3.94 g, 30.37 mmoles)were added and the mixture was refluxed for 24 h. After cooling to RT,the reaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as off-white solid (1.60 g, 47% yield). ¹H-NMR(δ ppm, CDCl₃, 400 MHz): δ 8.33(d, J=2.4Hz, 1H), 7.76(dd, J=8.8,2.4 Hz,1H), 7.38(d, J=8.8Hz, 1H), 7.24(dd, J=5.5,2.0Hz, 2H), 7.16 (dt,J=11.4,2.8 Hz, 2H), 2.61(q, J=7.6Hz, 2H), 1.27(t, J=7.5Hz, 3H).

Intermediate 54: 2-Ethyl-3-(4-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 53 (1.00 g, 2.88 mmoles) in ethanol (10ml), ammonium formate (1.70 g, 27.60 mmoles) and palladium on carbon(10%, 80 mg) were added and the solution was refluxed for 1 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated to afford the title compound as colourlessliquid (0.640 g, 83% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.24(dd,J=8.0,1.5Hz, 1H), 7.69(dt, J=8.6,1.7 Hz, 1H), 7.48(d, J=8.3Hz, 1H),7.41(t, J=7.9Hz, 1H), 7.24(m, 2H), 7.15(t, J=8.7Hz, 1H), 2.62(q,J=7.6Hz, 2H), 1.28 (t, J=7.6Hz,3H).

Intermediate 55: 2-(1-Bromoethyl)-3-(4-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 54 (0.600 g, 2.23 mmoles) in carbontetrachloride (15 ml) N-bromosuccinimide (0.398 g, 2.23 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (10 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off-white solid(1.10 g) which is taken as such for next step.

Intermediate 56: 2-Ethyl-6-fluoro-3-phenyl-4H-chromen-4-one

Intermediate 50 (3.0 g, 13.63 mmoles) was taken in a RB flask and tothis triethylamine (30 ml) and propionic anhydride (5.30 g, 40.78mmoles) were added and the mixture was refluxed for 24 h. After coolingto RT, the reaction mixture was acidified by the addition of 1N HClsolution, extracted with ethyl acetate, washed with sodium bicarbonatesolution, dried with sodium sulphate and concentrated. The crude productwas purified by column chromatography with ethyl acetate:petroleum etherto afford the title compound as off-white solid (2.27 g, 65% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.79(dd, J=7.1, 4.4Hz, 1H), 7.73(dt,J=7.7,3.1 Hz, 2H), 7.46(t, J=8.2Hz, 2H), 7.40(m, 1H), 7.27 (dd,J=8.2,1.4 Hz, 2H), 2.55(q, J=7.5Hz, 2H), 1.19(t, J=7.6Hz, 3H).

Intermediate 57: 2-(1-Bromoethyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of intermediate 56 (1.0 g, 3.72 mmoles) in carbontetrachloride (20 ml) N-bromosuccinimide (0.662 g, 3.72 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (10 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off-white solid(1.37 g). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.89(dd, J=9.2, 4.3Hz,1H), 7.79(dt, J=8.3,3.2 Hz, 2H), 7.73(dd, J=8.3.3.1Hz, 2H), 7.51-7.42(m,3H), 7.32(d, J=6.6 Hz, 2H), 4.97(q, J=6.8Hz, 1H), 1.96(d, J=6.8Hz, 3H).

Intermediate 58: 3-(3-Methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.522 g,2.0 mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml),3-methoxyphenylboronic acid (0.395 g, 2.59 mmoles) and sodium carbonate(1.05 g, 10 mmoles) were added and the system is degassed for 30 minPalladium tetrakis triphenylphosphine (0.455 g, 0.39 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture neutralised with 1.5N HCl, extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol:dichloromethane to afford the titlecompound as off-white solid (0.130 g, 27% yield). ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): δ 13.57(s, 1H), 8.20(s, 1H), 7.46(t, J=7.8Hz, 1H),7.23(d, J=7.5 Hz, 1H), 7.18(d, J=2.4Hz, 1H), 7.04 (dd, J=8.0,1.8 Hz,1H), 3.81(s, 3H).

Intermediate 59: 1-(2-Hydroxyphenyl)-2-phenylethanone

To a solution of intermediate 1 (1.00 g, 3.43 mmoles) in ethanol (10ml), ammonium formate (2.16 g, 34.34 mmoles) and palladium on carbon(10%, 100 mg) were added and the solution was refluxed for 1 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated to afford the title compound as colourlessliquid (0.560 g, 77% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 11.80(s,1H), 8.02(dd, J=5.7,1.7Hz, 1H), 7.54(dt, J=8.6,1.7 Hz, 1H), 7.33(m, 5H),6.98(m, 2H), 4.43(s, 2H).

Intermediate 60: 6-Bromo-2-ethyl-3-o-tolyl-4H-chromen-4-one

Intermediate 11 (3.0 g, 9.83 mmoles) was taken in a RB flask and to thistriethylamine (25 ml) and propionic anhydride (4.00 g, 30.76 mmoles)were added and the mixture was refluxed for 24 h. After cooling to RT,the reaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as colourless liquid (0.700 g, 20% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.73(d, J=2.5Hz, 1H), 7.63(dd,J=8.7, 2.5 Hz, 1H), 7.34(t, J=4.8Hz, 1H), 7.22-7.14(m, 4H), 2.63(q,J=7.5Hz, 2H), 0.94(t, J=7.5Hz, 3H).

Intermediate 61: 2-Ethyl-3-o-tolyl-4H-chromen-4-one

To a solution of intermediate 60 (0.950 g, 2.76 mmoles) in ethanol (15ml), ammonium formate (1.73 g, 27.60 mmoles) and palladium on carbon(10%, 80 mg) were added and the solution was refluxed for 1 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated to afford the title compound as colourlessliquid (0.620 g, 85% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ8.05(dd, J=7.9, 1.3Hz, 1H), 7.83(dt, J=8.5,1.5 Hz, 1H), 7.68(d, J=8.4Hz,1H), 7.50(t, J=7.5Hz, 1H), 7.30(d, J=4.3Hz, 2H), 7.26(m, 1H), 7.13(d,J=7.2Hz, 1H), 2.46(m, 2H), 1.15 (t, J=7.6Hz,3H).

Intermediate 62: 2-(2-Fluorophenyl)-1-(2-hydroxyphenyl)ethanone

To a solution of intermediate 23 (9.0 g, 29.13 mmoles) in ethanol (90ml), ammonium formate (18.3 g, 291.13 mmoles) and palladium on carbon(10%, 0.50 g) were added and the solution was refluxed for 1 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated. The crude product was purified by columnchromatography with ethyl acetate:petroleum ether to afford the titlecompound as colourless solid (3.5 g, 52% yield). ¹H-NMR (δ ppm, CDCl₃,400 MHz): δ 12.08(s, 1H), 7.90(d, J=7.0Hz, 1H), 7.51(dt, J=7.2,1.4 Hz,1H), 7.31-7.23(m,2H), 7.15-7.08(m,2H), 7.01(d, J=8.4Hz, 1H), 6.96(t,J=8.0Hz, 1H), 4.36(s, 2H).

Intermediate 63:tert-butyl(3-(2-fluorophenyl)-4-oxo-4H-chromen-2-yl)methyl carbamate

To a solution of intermediate 62 (2 g, 8.68 mmoles) in dichloromethane(20 ml), triethylamine (2.6 g, 26.06 mmoles) was added followed byN-Boc-Glycine (1.8 g, 10.27 mmoles). To this mixture HATU (6.6 g, 17.37mmoles) was added and stirred at RT for 12 h. The reaction mixture wasquenched by the addition of water and extracted with dichloromethane.The organic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with ethyl acetate: petroleum ether to afford the titlecompound as yellow solid (0.72 g, 23% yield). ¹H-NMR (δ ppm, DMSO-D₆,400 MHz): δ 8.06(d, J=6.7Hz, 1H), 7.87(dt, J=7.0,1.6 Hz, 1H), 7.62 (d,J=8.5 Hz, 1H), 7.53(t, J=7.4Hz, 1H), 7.48-7.35(m, 3H), 7.30(m,2H),4.04(d, J=5.9Hz, 2H),1.36(s, 9H).

Intermediate 64: 2-(Amino methyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 63 (0.700 g, 1.89 mmoles) indichloromethane (10 ml), trifluoroacetic acid (3 ml) was added andstirred at RT for 2 h. The reaction mixture was concentrated, basifiedwith sodium bicarbonate solution, extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the title compound as brown liquid (0.440 g,86%). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.06(d, J=7.9Hz, 1H), 7.87(dt,J=8.5,1.3Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52(m,2H), 7.40(t, J=7.2Hz,1H), 7.31(m,2H), 3.51(s,2H).

Intermediate 65: 2-(3-Fluorophenyl)-1-(2-hydroxyphenyl)ethanone

To a solution of intermediate 33 (11.0 g, 35.58 mmoles) in ethanol (110ml), ammonium formate (22.4 g, 355.83 mmoles) and palladium on carbon(10%, 0.550 g) were added and the solution was refluxed for 1 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated. The crude product was purified by columnchromatography with ethyl acetate:petroleum ether to afford the titlecompound as colourless solid (5.6 g, 70% yield). ¹H-NMR (δ ppm, DMSO-D₆,400 MHz): δ 11.68(s, 1H), 8.00(dd, J=8.3,1.6Hz, 1H), 7.54(dt, J=8.5,1.6Hz, 1H), 7.38(m,1H), 7.14-7.04 (m,3H), 6.99(m, 2H), 4.48(s, 2H).

Intermediate 66: 1-(5-Fluoro-2-hydroxyphenyl)-2-(2-fluorophenyl)ethanone

2-Fluorophenylacetic acid (2.0 g, 13.14 mmoles) was dissolved in 20 mldichloromethane. To this mixture, oxalylchloride (1.66 g, 13.14 mmoles)and DMF (3 drops) were added at 0° C. and stirred for 30 min. Thesolvent was evaporated and dissolved in 20 ml dichloromethane. To thismixture, 4-fluoroanisole (1.10 g, 8.76 mmoles) was added and cooled to0° C. At 0° C. AlCl₃ (1.75 g, 13.14 mmoles) was added and the reactionmixture was warmed to RT and stirred for 12 h. The reaction mixture wasquenched by the addition of 2N HCl, extracted with ethyl acetate, driedover sodium sulphate and concentrated. The crude product was purified bycolumn chromatography with ethyl acetate:petroleum ether to afford thetitle compound as off-white solid (1.17 g, 54% yield. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 11.25(s,1H), 7.73(dd, J=9.5,3.2Hz, 1H), 7.43(dt,J=8.8,3.1Hz, 1H), 7.35(d, J=6.2Hz, 1H), 7.31(d, J=7.2Hz, 1H), 7.19(d,J=8.2 Hz, 1H), 7.03(dd, J=9.1,4.6 Hz, 1H),4.50(s, 2H).

Intermediate 67: 2-Ethyl-6-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one

Intermediate 66 (1.1 g, 4.43 mmoles) was taken in a RB flask and to thistriethylamine (10 ml) and propionic anhydride (1.80 g, 13.86 mmoles)were added and the mixture was refluxed for 24 h. After cooling to RT,the reaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as off-white solid (0.800 g, 63% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.82(dd, J=9.0,4.4Hz, 1H),7.75(m,2H), 7.50(m,1H), 7.37-7.28(m, 3H), 2.56(m,2H), 1.19(t, J=7.6Hz,3H).

Intermediate 68:2-(1-bromoethyl)-6-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 67 (0.790 g, 2.75 mmoles) in carbontetrachloride (15 ml) N-bromosuccinimide (0.491 g, 2.75 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (10 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as yellow solid(0.824 g). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ [7.93(d, J=4.3Hz,)7.91(d, J=4.2Hz), 1H], 7.83(dt, J=8.2,3.1 Hz, 1H), 7.75(m, 1H), 7.56(m,1H), 7.41(m, 3H), [5.00(q, J=6.9Hz), 4.93(q, J=6.9Hz, 1H], [1.99(d,J=6.9Hz), 1.95(d, J=6.8Hz),3H).

Intermediate 69:1-(5-bromo-2-hydroxyphenyl)-2-(3,5-difluorophenyl)ethanone

3,5-Difluorophenylacetic acid (5.0 g, 29.0 mmoles) was dissolved in 50ml dichloromethane. To this mixture, oxalylchloride (3.8 ml, 43.57mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min.The solvent was evaporated and dissolved in 50 ml dichloromethane. Tothis mixture, 4-bromooanisole (5.42 g, 29.0 mmoles) was added and cooledto 0° C. At 0° C. AlCl₃ (5.80 g, 47.57 mmoles) was added and thereaction mixture was warmed to RT and stirred for 12 h. The reactionmixture was quenched by the addition of 2N HCl, extracted with ethylacetate, dried over sodium sulphate and concentrated. The crude productwas purified by column chromatography with ethyl acetate:petroleum etherto afford the title compound as off-white solid (7.21 g, 77% yield.¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 11.44(s,1H), 7.98(d, J=2.5Hz, 1H),7.65(dd, J=8.9,2.6Hz, 1H), 7.13(tt, J=9.1,2.4Hz, 1H), 7.02(m,3H),4.50(s,2H).

Intermediate 70: 2-(3,5-Difluorophenyl)-1-(2-hydroxyphenyl)ethanone

To a solution of intermediate 69 (7.20 g, 22.01 mmoles) in ethanol (70ml), ammonium formate (13.8 g, 220.17 mmoles) and palladium on carbon(10%, 0.250 g) were added and the solution was refluxed for 1 h. Thesolution was filtered through celite, diluted with ethyl acetate, washedwith 10% sodium bicarbonate solution (100 ml), dried over sodiumsulphate and concentrated to afford the title compound as yellow solid(4.1 g, 76% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 11.58(s, 1H),7.97(dd, J=8.3,1.6Hz, 1H), 7.55(dt, J=8.5,1.5Hz, 1H), 7.14 (tt,J=7.5,2.2Hz, 1H), 7.03-6.96(m,4H), 4.52(s, 2H).

Intermediate 71: 3-(3,5-Difluorophenyl)-2-ethyl-4H-chromen-4-one

Intermediate 70 (2.0 g, 8.08 mmoles) was taken in a RB flask and to thistriethylamine (20 ml) and propionic anhydride (3.26 g, 25.2 mmoles) wereadded and the mixture was refluxed for 24 h. After cooling to RT, thereaction mixture was acidified by the addition of 1N HCl solution,extracted with ethyl acetate, washed with sodium bicarbonate solution,dried with sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate:petroleum ether toafford the title compound as off-colourless liquid (1.65 g, 72% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.05(dd, J=7.9,1.2Hz, 1H), 7.8 (dt,J=8.5,1.4Hz, 1H), 7.68(d, J=8.4Hz, 1H), 7.51(t, J=7.8Hz, 1H), 7.30(tt,J=7.2,2.2Hz, 1H), 7.07(d, J=6.1Hz, 2H), 2.58(q, J=7.5Hz, 1H), 1.21(t,J=7.6Hz, 3H).

Intermediate 72:2-(1-Bromoethyl)-3-(3,5-difluorophenyl)-4H-chromen-4-one

To a solution of intermediate 71 (1.60 g, 5.58 mmoles) in carbontetrachloride (20 ml) N-bromosuccinimide (0.994 g, 5.58 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (30 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as brown solid (1.95g, 96% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.06(dd, J=7.9,1.5Hz,1H), 7.90(dt, J=8.6,1.6Hz, 1H), 7.78(d, J=8.3 Hz, 1H), 7.55(t, J=7.3Hz,1H), 7.38(tt, J=9.5,2.3Hz, 1H), 7.10(dd, J=8.3,2.2Hz, 2H), 5.05(q,J=6.8Hz, 1H), 1.97(d, J=6.8Hz,3H).

Intermediate 73: 1-(5-Fluoro-2-hydroxyphenyl)-2-(3-fluorophenyl)ethanone

3-Fluorophenylacetic acid (7.33 g, 47.56 mmoles) was dissolved in 25 mldichloromethane. To this mixture, oxalylchloride (7.54 g, 59.46 mmoles)and DMF (3 drops) were added at 0° C. and stirred for 30 min. Thesolvent was evaporated and dissolved in 25 ml dichloromethane. To thismixture, 4-fluoroanisole (5.00 g, 39.64 mmoles) was added and cooled to0° C. At 0° C. AlCl₃ (7.95 g, 59.46 mmoles) was added and the reactionmixture was warmed to RT and stirred for 12 h. The reaction mixture wasquenched by the addition of 2N HCl, extracted with ethyl acetate, driedover sodium sulphate and concentrated. The crude product was purified bycolumn chromatography with ethyl acetate:petroleum ether to afford thetitle compound as colourless solid (4.5 g, 45% yield. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 11.34(s,1H), 7.75(dd, J=9.4,3.1Hz, 1H), 7.42(m,2H), 7.12(m, 3H), 7.05(dd, J=9.0,4.5Hz, 1H), 4.47(s, 2H).

Intermediate 74: 2-Ethyl-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

Intermediate 73 (3.00 g, 12.08 mmoles) was taken in a RB flask and tothis triethylamine (25 ml) and propionic anhydride (4.92 g, 37.82mmoles) were added and the mixture was refluxed for 24 h. After coolingto RT, the reaction mixture was acidified by the addition of 1N HClsolution, extracted with ethyl acetate, washed with sodium bicarbonatesolution, dried with sodium sulphate and concentrated. The crude productwas purified by column chromatography with ethyl acetate:petroleum etherto afford the title compound as off-yellow solid (1.80 g, 52% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.80(m, 1H), 7.76(m,2H), 7.51(dd,J=8.0,6.4Hz), 7.22(m,1H), 7.18(m, 2H), 2.56(q, J=7.6Hz, 2H), 1.20(t,J=7.6Hz, 3H).

Intermediate 75:2-(1-Bromoethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 74 (1.80 g, 6.28 mmoles) in carbontetrachloride (20 ml) N-bromosuccinimide (1.11 g, 6.28 mmoles) was addedand heated to 80° C. Azobisisobutyronitrile (10 mg) was added to thereaction mixture at 80° C. After 12 h, the reaction mixture was cooledto RT, diluted with dichloromethane and washed with water. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure to afford the crude title compound as yellow solid (1.25 g, 55%yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.91(dd, J=9.2,4.3Hz, 1H),7.81(dt, J=8.2,2.8Hz, 1H), 7.74(dd, J=8.3,3.1 Hz, 1H), 7.57(m, 1H),7.32(dt, J=8.5,2.4Hz, 1H),7.19(m, 2H), 5.00(q, J=6.8Hz, 1H),1.97(d,J=6.8Hz,3H).

Intermediate 76: 3-(3-fluorophenyl)-2-methyl-4H-chromen-4-one

Intermediate 65 (1.50 g, 6.51 mmoles) was taken in a RB flask and tothis acetic anhydride (15 ml) and sodium acetate (3.74 g, 45.60 mmoles)were added and the mixture was refluxed for 12 h. After cooling to RT,the reaction mixture was quenched by the addition of ice cold water. Thesolid formed was filtered and washed with water. The product was driedunder vacuum to afford the title compound as colourless solid (1.1 g,68% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.05(dd, J=7.9,1.6Hz,1H), 7.83(m,1H), 7.66(d, J=8.1 Hz, 1H), 7.50(m, 2H), 7.24-7.13(m, 3H),2.29(s, 3H).

Intermediate 77: 2-(bromomethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 76 (1.00 g, 3.99 mmoles) in carbontetrachloride (10 ml) N-bromosuccinimide (0.711 g, 3.99 mmoles) wasadded and heated to 80° C. Azobisisobutyronitrile (10 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as off-white solid(0.990 g, 74% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.07(dd,J=8.1,1.6Hz, 1H), 7.89(m,1H), 7.73(d, J=8.3Hz, 1H), 7.56(m, 2H),7.32(dt, J=8.4,2.3Hz, 1H), 7.23(m, 2H), 4.40(s,2H).

Intermediate 78: 3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.50 g,5.74 mmoles) in DMF (12 ml), ethanol (7 ml) and water (7 ml),3-Fluorophenyl boronic acid (1.6 g, 11.49 mmoles) and sodium carbonate(3.0 g, 28.73 mmoles) were added and the system is degassed for 30 min.Palladium tetrakis triphenylphosphine (1.90 g, 1.72 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture neutralised with 1.5N HCl, extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.240 g, 18% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.66(s, 1H), 8.21(s, 1H), 7.59(m, 1H), 7.50(d, J=7.6,1.2Hz,1H), 7.45(m,1H),7.31(m, 1H).

Intermediate 79:3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.700 g,2.68 mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml),3-Fluoro-5-methoxyphenyl boronic acid (0.592 g, 3.48 mmoles) and sodiumcarbonate (1.42 g, 13.40 mmoles) were added and the system is degassedfor 30 min Palladium tetrakis triphenylphosphine (0.588 g, 0.509 mmoles)was added under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.260 g, 37% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.64(s, 1H), 8.21(s, 1H), 7.03(m, 2H), 6.93(td,J=11.1,2.3Hz, 1H),3.83(s, 3H).

Intermediate 80:3-(4-Fluoro-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g,1.91 mmoles) in DMF (8 ml), ethanol (4 ml) and water (4 ml),4-Fluoro-3-methoxyphenyl boronic acid (0.423 g, 2.49 mmoles) and sodiumcarbonate (1.01 g, 9.57 mmoles) were added and the system is degassedfor 30 min Tetrakis triphenylphosphine Palladium (0.436 g, 0.377 mmoles)was added under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.240 g, 48% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.64(s, 1H), 8.20(s, 1H), 8.08(s, 1H), 7.54(d, J=9.3Hz,1H), 7.34(d, J=8.3Hz, 1H),3.82(s, 3H).

Intermediate 81:3-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g,3.83 mmoles) in DMF (12 ml), ethanol (7 ml) and water (7 ml),3-Fluoro-4-methoxyphenyl boronic acid (0.781 g, 4.59 mmoles) and sodiumcarbonate (2.03 g, 19.15 mmoles) were added and the system is degassedfor 30 min Tetrakis triphenylphosphine Palladium (0.872 g, 0.754 mmoles)was added under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as brown solid (0.136 g, 14% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.53(s, 1H), 8.19(s, 1H), 7.45(m, 2H), 7.33(t, J=8.6Hz,1H), 3.89(s, 3H).

Intermediate 82:3-(3-chloro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.700 g,2.68 mmoles) in DMF (10 ml), ethanol (6 ml) and water (6 ml),3-chloro-5-methoxyphenyl boronic acid (0.600 g, 3.21 mmoles) and sodiumcarbonate (1.40, 13.40 mmoles) were added and the system is degassed for30 min Tetrakis triphenylphosphine Palladium (0.610 g, 0.528 mmoles) wasadded under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.198 g, 27% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.66(s, 1H), 8.21(s, 1H), 7.24(t, J=1.6Hz, 1H), .7.13(d,J=1.2Hz, 1H), 7.11(t, J=2.1Hz, 1H), 3.83(s, 3H).

Intermediate 83:3-(3-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g,3.83 mmoles) in DMF (14 ml), ethanol (7 ml) and water (7 ml),3-trifluoromethoxyphenyl boronic acid (1.025 g, 4.97 mmoles) and sodiumcarbonate (2.02 g, 19.15 mmoles) were added and the system is degassedfor 30 min Tetrakis triphenylphosphine Palladium (0.871 g, 0.754 mmoles)was added under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.465 g, 41% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.71(s, 1H), 8.22(s, 1H), 7.70(m, 2H), .7.59(s, 1H),7.46(td, J=7.9,1.4Hz, 1H).

Intermediate 84: 3-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g,3.83 mmoles) in DMF (14 ml), ethanol (7 ml) and water (7 ml),4-methoxyphenyl boronic acid (0.873 g, 5.746 mmoles) and sodiumcarbonate (2.03 g, 19.15 mmoles) were added and the system is degassedfor 30 min. Tetrakis triphenylphosphine Palladium (0.871 g, 0.754mmoles) was added under nitrogen atmosphere and heated to 80° C. After12 h, the reaction mixture was celite filtered, concentrated andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol:dichloromethane toafford the title compound as off-white solid (0.250 g, 27% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 13.46(s, 1H), 8.19(s, 1H), 7.59(td,J=9.5,2.8Hz, 2H), .7.11(td, J=11.6,2.6, 2H),3.81(s,3H).

Intermediate 85:3-(4-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g,3.83 mmoles) in DMF (14 ml), ethanol (7 ml) and water (7 ml),4-fluoro-2-methoxyphenyl boronic acid (0.846 g, 4.979 mmoles) and sodiumcarbonate (2.06 g, 19.15 mmoles) were added and the system is degassedfor 30 min Tetrakis triphenylphosphine Palladium (0.754 g, 0.652 mmoles)was added under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as off-white solid (0.350 g, 35% yield). ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): δ 13.46(s, 1H), 8.14(s, 1H), 7.40(t, J=8.4Hz, 1H),7.09(dd, J=11.5,2.9Hz, 1H),6.91(dt, J=8.4,2.4Hz 1H),3.78(s,3H).

Intermediate 86:3-(4-chloro-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.430 g,1.65 mmoles) in DMF (3.6 ml), ethanol (1.8 ml) and water (1.8 ml),4-chloro-3-methoxyphenyl boronic acid (0.400 g, 2.145 mmoles) and sodiumcarbonate (0.873 g, 19.15 mmoles) were added and the system is degassedfor 30 min Tetrakis triphenylphosphine Palladium (0.374 g, 0.313 mmoles)was added under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as green solid (0.060 g, 10% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.62(s, 1H), 8.20(s, 1H), 7.56(d, J=8.1Hz, 1H), 7.34(s,1H),7.23(d, J=8.1Hz 1H),3.91(s,3H).

Intermediate 87:3-(2-chloro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0770 g,4.12 mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml),2-chloro-5-methoxyphenyl boronic acid (1.00 g, 5.364 mmoles) and sodiumcarbonate (2.186 g, 20.63 mmoles) were added and the system is degassedfor 30 min Tetrakis triphenylphosphine Palladium (0.905 g, 0.783 mmoles)was added under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as green solid (0.090 g, 16% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.61(s, 1H), 8.19(s, 1H), 7.51(d, J=8.9Hz, 1H), 7.09(d,J=8.9Hz 1H), 7.06(d, J=2.6Hz 1H), 3.78(s,3H).

Intermediate 88:3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g,3.83 mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml),3,4-dimethoxyphenyl boronic acid (1.04 g, 5.746 mmoles) and sodiumcarbonate (2.03 g, 19.15 mmoles) were added and the system is degassedfor 30 min Tetrakis triphenylphosphine Palladium (0.872 g, 0.754 mmoles)was added under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.220 g, 21% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.46(s, 1H), 8.19(s, 1H), 7.20(s,1H), 7.19(d, J=9.3Hz, 1H),7.11(d, J=8.1Hz 1H), 3.81(s,6H).

Intermediate 89: 6-fluoro-2-methyl-3-phenyl-4H-chromen-4-one

Intermediate 50 (50 g, 0.217 moles) was taken in a RB flask and to thisacetic anhydride (424 ml) and sodium acetate (124 g, 1.51 moles) wereadded and the mixture was refluxed for 12 h. After cooling to RT, thereaction mixture was quenched by the addition of ice cold water. Thesolid formed was filtered and washed with water. The product was driedunder vacuum to afford the title compound as colourless solid (44 g, 80%yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 7.87(dd, J=8.3,3.0 Hz, 1H),7.47-7.35(m,5H), 7.29(m, 2H), 2.32(s, 3H).

Intermediate 90: 2-(bromomethyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of intermediate 89 (44 gg, 0.16 moles) in carbontetrachloride (400 ml) N-bromosuccinimide (29.1 g, 0.16 moles) was addedand heated to 80° C. Azobisisobutyronitrile (500 mg) was added to thereaction mixture at 80° C. After 12 h, the reaction mixture was cooledto RT, diluted with dichloromethane and washed with water. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure to afford the crude title compound as pale yellow solid (40.2g, 75% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.87(dd, J=8.1,3.0Hz,1H), 7.55(dd, J=9.1,4.2Hz, 1H), 7.50-7.37(m,6H), 4.24(s,2H).

Intermediate 91: 6-fluoro-3-(3-fluorophenyl)-2-methyl-4H-chromen-4-one

Intermediate 73 (24 g, 0.096 moles) was taken in a RB flask and to thisacetic anhydride (230 ml) and sodium acetate (55.2 g, 0.673 moles) wereadded and the mixture was refluxed for 12 h. After cooling to RT, thereaction mixture was quenched by the addition of ice cold water. Thesolid formed was filtered and washed with water. The product was driedunder vacuum to afford the title compound as brown solid (26 g, quant.yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 7.87(dd, J=8.2,3.0 Hz, 1H),7.48-7.36(m,3H), 7.10-6.99(m, 3H), 2.33(s, 3H).

Intermediate 92:2-(bromomethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 91 (39 g, 0.143 moles) in carbontetrachloride (400 ml) N-bromosuccinimide (25.5 g, 0.143 moles) wasadded and heated to 80° C. Azobisisobutyronitrile (500 mg) was added tothe reaction mixture at 80° C. After 12 h, the reaction mixture wascooled to RT, diluted with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the crude title compound as pale brown solid(27 g, 54% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.87(dd,J=8.1,3.0Hz, 1H), 7.69 (dd, J=9.2,5.1Hz, 1H), 7.49(m,2H),7.18-7.10(m,3H),4.23(s,2H).

Intermediate 93: 1-(4-bromo-2-fluorophenyl)ethanol

To a ice-cold solution of methyl magnesium iodide prepared frommagnesium (1.7 g, 73.88 mmoles) and methyl iodide (4.58 ml, 73.88mmoles) in diethyl ether (50 ml), 4-bromo-2-fluorobenzaldehyde (5 g,24.62 mmoles) in diethyl ether (10 ml) was added and warmed to roomtemperature. After 12 h, the reaction mixture was cooled to 0° C.,quenched with dilute HCl and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure to afford the title compound as red colour liquid (5 g, 94%yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 7.40(t, J=8.2Hz, 1H), 7.30(dd,J=8.3,1.7Hz, 1H), 7.21(dd, J=9.9,1.9Hz, 1H), 5.17(q, J=6.4Hz, 1H),1.49(d, J=6.5Hz, 3H).

Intermediate 94: 1-(4-bromo-2-fluorophenyl)ethanone

To a solution of intermediate 93 (5.0 g, 22.82 mmoles) in DMF (25 ml),pyridinium dichromate (12.8 g, 34.23 mmoles) was added at roomtemperature. After 12 h, the reaction mixture was quenched with water,diluted with ethyl acetate. And filtered through celite. The organiclayer was washed with brine solution and dried over sodium sulphate andconcentrated under reduced pressure to afford the title compound as redcolour liquid (4.1 g, 84% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ7.76(t, J=8.3Hz, 1H), 7.73(dd, J=10.8,1.8Hz, 1H), 7.55(dd, J=5.2,1.8Hz,1H), 2.55(s,3H).

Intermediate 95: 6-bromo-3-methyl-1H-indazole

To a solution of intermediate 94 (3.7 g, 17.04 mmoles) in 1,2-ethanediol(25 ml), hydrazine hydrate (1.65 ml, 34.09 mmoles) was added at roomtemperature and heated to 165° C. After 12 h, the reaction mixturecooled to room temperature, quenched with water and solid precipitatedwas filtered and dried under vacuum to afford the title compound ascolourless solid (2.5 g, 72% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ12.74(s,1H), 7.67(d, J=5.8Hz, 1H), 7.65(s, 1H), 7.19(dd, J=8.6,1.4Hz,1H), 2.46(s,3H).

Intermediate 96: tert-butyl 6-bromo-3-methyl-1H-indazole-1-carboxylate

To a solution of intermediate 95 (10.0 g, 47.39 mmoles) in acetonitrile(100 ml) cooled to 20° C., Boc-anhydride (10.3 g, 34.09 mmoles) wasadded followed by DMAP (0.579 g, 4.73 mmoles) and triethylamine (4.7 g,47.39 mmoles) and the reaction mixture was stirred at room temperature.After 12 h, the reaction mixture was concentrated and quenched withwater and solid precipitated was filtered and dried under vacuum toafford the title compound as colourless solid (10.3 g, 70% yield).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.19(d, J=1.2Hz, 1H), 7.81(d,J=8.4Hz, 1H),), 7.54(dd, J=8.5,1.7Hz, 1H), 2.50(s,3H),1.62(s,9H).

Intermediate 97:3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

To a solution of intermediate 95 (1.0 g, 4.73 mmoles) in Dioxan 16 ml),bis(pinacaloto)diboron (1.3 g, 5.21 mmoles) and potassium acetate (0.930g, 9.47 mmoles) were added and the system is degassed for 30 minBis(diphenylphosphinoferrocene)dichloro palladium.CH₂Cl₂ (0.387 g, 0.473mmoles) was added under nitrogen atmosphere and heated to 80° C. After12 h, the reaction mixture filtered through celite and concentrated. Thecrude product was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as off-white solid(1.1 g, 91% yield) which is used as such for the next step.

Intermediate 98: tert-butyl3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate

To a solution of intermediate 96 (2.70 g, 8.67 mmoles) in Dioxan (44ml), bis(pinacaloto)diboron (2.4 g, 9.54 mmoles) and potassium acetate(1.70 g, 17.35 mmoles) were added and the system is degassed for 30 minBis(diphenylphosphinoferrocene)dichloro palladium.CH₂Cl₂ (0.354 g, 0.433mmoles) was added under nitrogen atmosphere and heated to 80° C. After12 h, the reaction mixture filtered through celite and concentrated. Thecrude product was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as off-white solid(2.70 g, 87% yield).). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.46(s,1H),7.82(d, J=7.9Hz, 1H), 7.61(d, J=8.0Hz, 1H),), 2.51(s,3H),1.62(s,9H).

Intermediate 99: 1-(4-bromo-2-fluorophenyl)propan-1-ol

To a ice-cold solution of ethyl magnesium iodide prepared from magnesium(2.39 g, 98.51 mmoles) and ethyl iodide (7.88 ml, 98.51 mmoles) indiethyl ether (50 ml), 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmoles)in diethyl ether (10 ml) was added and warmed to room temperature. After12 h, the reaction mixture was cooled to 0° C., quenched with dilute HCland extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure to afford thetitle compound as red colour liquid (5.8 g, 99% yield) which is used assuch for step.

Intermediate 100:1-(4-bromo-2-fluorophenyl)propan-1-one

To a solution of intermediate 99 (5.8 g, 24.89 mmoles) in DMF (30 ml),pyridinium dichromate (14.04 g, 37.33 mmoles) was added at roomtemperature. After 12 h, the reaction mixture was quenched with water,diluted with ethyl acetate and filtered through celite. The organiclayer was washed with brine solution and dried over sodium sulphate andconcentrated under reduced pressure to afford the title compound ascolourless liquid (4.4 g, 76% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 7.78(t, J=8.1Hz, 1H), 7.38(m, 2H), 2.55(m,2H), 1.21(t, J=7.1Hz, 3H).

Intermediate 101: 6-bromo-3-ethyl-1H-indazole

To a solution of intermediate 100 (4.3 g, 18.53 mmoles) in DMSO (4.5ml), hydrazine hydrate 17.3 ml, 357.7 mmoles) was added at roomtemperature and heated to 130° C. After 22 h, the reaction mixturecooled to room temperature, quenched with water and solid precipitatedwas filtered and dried under vacuum to afford the title compound ascolourless solid (3.8 g, 91% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ12.73(s,1H), 7.70(d, J=8.6Hz, 1H), 7.66(d, J=1.1Hz, 1H), 7.18(dd,J=8.5,1.5Hz, 1H), 2.92(q, J=7.6Hz, 2H), 1.30(t, J=7.6Hz, 3H).

Intermediate 102: tert-butyl 6-bromo-3-ethyl-1H-indazole-1-carboxylate

To a solution of intermediate 101 (3.0 g, 13.32 mmoles) in acetonitrile(30 ml) cooled to 20° C., Boc-anhydride (5.81 g, 26.65 mmoles) was addedfollowed by DMAP (0.162 g, 1.33 mmoles) and triethylamine (1.34 g, 13.32mmoles) and the reaction mixture was stirred at room temperature. After12 h, the reaction mixture was concentrated and quenched with water andsolid precipitated was filtered and dried under vacuum to afford thetitle compound as colourless solid (4.04 g, 93% yield). ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): δ 8.31(s, 1H), 7.54(d, J=8.4Hz, 1H),), 7.42(dd,J=8.4,1.3Hz, 1H), 2.99(q, J=7.6Hz, 2H), 1.71(s,9H), 1.42(t, J=7.6Hz,3H).

Intermediate 103: tert-butyl3-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate

To a solution of intermediate 102 (1.50 g, 4.61 mmoles) in Dioxan (24ml), bis(pinacaloto)diboron (1.40 g, 5.53 mmoles) and potassium acetate(0.9050 g, 9.22 mmoles) were added and the system is degassed for 30 minBis(diphenylphosphinoferrocene)dichloro palladium.CH₂Cl₂ (0.188 g, 0.230mmoles) was added under nitrogen atmosphere and heated to 80° C. After12 h, the reaction mixture filtered through celite and concentrated. Thecrude product was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as off-white solid(1.46 g, 85% yield).). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.47(s, 1H),7.86(d, J=7.9Hz, 1H),), 7.60(d, J=8.0Hz, 1H), 2.98(q, J=7.6Hz, 2H),1.62(s,9H), 1.31(s,12H), 1.30(t, J=7.6Hz, 3H).

Intermediate 104: 6-bromo-3-hydroxy-3-methylindolin-2-one

To a ice-cold solution of methyl magnesium iodide prepared frommagnesium (1.7 g, 70.78 mmoles) and methyl iodide (4.40 ml, 70.78mmoles) in diethyl ether (60 ml), 6-bromoisatin (4 g, 17.69 mmoles) inTHF (120 ml) was added and warmed to room temperature. After 12 h, thereaction mixture was cooled to 0° C., quenched with dilute HCl andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure to afford the titlecompound as brown solid (4.2 g, 93% yield). ¹H-NMR (δ ppm, CDCl₃, 400MHz): δ 10.34(s,1H), 7.23(t, J=7.9Hz, 1H), 7.14(dd, J=7.9,1.7Hz, 1H),6.93(d, J=1.6Hz, 1H), 5.92(s, 1H), 1.33(s, 3H).

Intermediate 105: 6-bromo-3-methyl-1H-indole

To a solution of intermediate 104 (3.0 g, 12.48 mmoles) in THF (120 ml)cooled to 0° C., boron-dimethylsulfide (2M in THF, 62.44 mmoles) wasadded and heated to 50° C. After 12 h, the reaction mixture was cooledto 0° C., quenched with methanol and concentrated. The crude product waspurified by column chromatography with ethyl acetate: petroleum ether toafford the title compound as off-white solid (1.15 g, 44% yield). ¹H-NMR(δ ppm, CDCl₃, 400 MHz): δ 10.85(s,1H), 7.48(d, J=1.8Hz, 1H), 7.42(d,J=8.4Hz, 1H), 7.12(t, J=1.1Hz, 1H), 7.09(dd, J=8.4,1.8Hz, 1H), 2.22(s,3H).

Intermediate 106:3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-O-1H-indole

To a solution of intermediate 105 (1.10 g, 5.23 mmoles) in Dioxan (33ml), bis(pinacaloto)diboron (1.60 g, 6.28 mmoles) and potassium acetate(1.54 g, 15.70 mmoles) were added and the system is degassed for 30 minBis(diphenylphosphinoferrocene)dichloro palladium.CH₂Cl₂ (0.128 g, 0.157mmoles) was added under nitrogen atmosphere and heated to 80° C. After12 h, the reaction mixture filtered through celite and concentrated. Thecrude product was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as off-white solid(0.651 g, 48% yield).). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 10.81(s,1H),7.68(s, 1H), 7.45(d, J=7.9Hz, 1H),), 7.28(d, J=7.9Hz, 1H), 7.19(s,1H),2.23(s,3H),1.28(s,12H).

Intermediate 107:3-(2,3-dihydrobenzofuran-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.70 g,2.68 mmoles) in DMF (10 ml), ethanol (6 ml) and water (6 ml),2,3-dihydrobenzofuran-5-boronic acid (0.527 g, 3.21 mmoles) and sodiumcarbonate (0.852 g, 8.04 mmoles) were added and the system is degassedfor 30 min Tetrakistriphenylphosphine Palladium (0.610 g, 0.528 mmoles)was added under nitrogen atmosphere and heated to 80° C. After 12 h, thereaction mixture was celite filtered, concentrated and extracted withethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as brown solid (0.198 g, 29% yield ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): δ 13.42(s,1H), 8.18(s,1H), 7.48(s,1H), 7.36(d, J=8.1Hz, 1H),6.90(d, J=8.2Hz, 1H), 4.61(d, J=8.7Hz, 2H),3.27(d, J=8.7Hz, 2H).

Intermediate 108: tert-butyl6-bromo-2-methyl-1H-benzo[d]imidazole-1-carboxylate

To a solution of 6-bromo-2-methylbenzimidazole (1.00 g, 4.737 mmoles) indichloromethane (20 ml) cooled to 20° C., Boc-anhydride (1.034 g, 4.737mmoles) was added followed by DMAP (0.057 g, 0.473 mmoles) andtriethylamine (0.479 g, 4.73 mmoles) and the reaction mixture wasstirred at room temperature. After 12 h, the reaction mixture wasconcentrated and quenched with water and solid precipitated was filteredand dried under vacuum to afford the title compound as colourless solidas a mixture of two regioisomers (1.22 g, 83% yield). ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): δ 8.00(d, J=1.9Hz, 0.53H), 7.80(d, J=7.5Hz, 0.47H),7.78(s, 0.47H), 7.55(d, J=8.5Hz, 0.53H), 7.47(m,1H), 2.69(s,1.4H),2.68(s, 1.6H), 1.63(s,9H).

Intermediate 109: tert-butyl2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate

To a solution of intermediate 108 (0.500 g, 1.606 mmoles) in Dioxan (24ml), bis(pinacaloto)diboron (0.489 g, 1.928 mmoles) and potassiumacetate (0.946 g, 9.64 mmoles) were added and the system is degassed for30 min. Bis(diphenylphosphinoferrocene)dichloro palladium.CH₂Cl₂ (0.196g, 0.241 mmoles) was added under nitrogen atmosphere and heated to 80°C. After 12 h, the reaction mixture filtered through celite andconcentrated. The crude product was purified by column chromatographywith ethyl acetate:petroleum ether to afford the title compound as brownsolid as a mixture of two regioisomers (0.324 g, 56% yield).). ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 8.42(s,0.65H), 8.15(s,0.35H), 7.92(d, J=8.3Hz,0.35H), 7.78(d, J=8.1Hz, 1H), 7.69(d, J=7.9Hz, 0.65H), 2.88(s, 3H),1.72(s,5.85H), 1.71(s,3.15H), 1.35(s,12H).

Intermediate 110: 4-bromo-2,6-difluorophenol

To a solution of 2,6-Difluorophenol (10.0 g, 76.86 mmoles) in DMF (60mll), N-bromosuccinimide (13.68 g, 76.86 mmoles) was added at 0° C. andstirred at RT for 20 h. The reaction mixture was concentrated, dilutedwith water and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure to affordthe title compound as light yellow liquid (15.1 g, 93% yield). ¹H-NMR (δppm, DMSO-D₆, 400 MHz): δ 10.49(s,1H), 7.35 (d, J=6.2 Hz, 2H).

Intermediate 111: 5-bromo-1,3-difluoro-2-methoxybenzene

To a solution of intermediate 110 (15.0 g, 71.73 mmoles) in acetone (60mll), potassium carbonate (29.75 g, 215.32 mmoles) was added at 0° C.followed by methyl iodide (22 ml, 358.86 mmoles) and stirred at RT for22 h. The reaction mixture was concentrated, diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure to afford the titlecompound as light yellow liquid (11 g, 68% yield). ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 7.08 (d, J=7.8 Hz, 2H).

Intermediate 112:2-(3,5-difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of intermediate 111 (2.0 g, 8.968 mmoles) in Dioxan (40ml), bis(pinacaloto)diboron (2.73 g, 10.76 mmoles) and potassium acetate(2.64 g, 26.90 mmoles) were added and the system is degassed for 30 minBis(diphenylphosphinoferrocene)dichloro palladium.CH₂Cl₂ (0.219 g, 0.269mmoles) was added under nitrogen atmosphere and heated to 80° C. After12 h, the reaction mixture filtered through celite and concentrated. Thecrude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as yellow liquid (2.2 g,90% yield).). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ δ 7.318 (d, J=8.7 Hz,2H), 4.02(s, 3H), 1.32(s,12H).

Intermediate 113:3-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 3.83mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml), intermediate112 (1.55 g, 5.74 mmoles) and sodium carbonate (1.21 g, 11.49 mmoles)were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.221 g, 0.19 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.210 g, 19% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 13.66(s,1H), 8.20(s,1H), 7.36(d, J=8.9Hz, 2H), 6.96(br s,2H), 3.97(s,3H).

Intermediate 114: 6-bromo-1,3-dimethyl-1H-indazole(a) and6-bromo-2,3-dimethyl-2H-indazole(b)

To a solution of intermediate 95 (2 g, 9.47 mmoles) in THF (30 ml)cooled to 0° C., sodium hydride (0.454 g, 60% in paraffin oil, 11.37mmoles) was added and stirred for 10 min Methyl iodide (2.0 gl, 14.21mmoles) was added warmed to room temperature. After 12 h, the reactionmixture cooled to room temperature, quenched with water, extracted withethyl acetate and concentrated. The crude product was purified by columnchromatography with ethyl acetate:petroleum ether to afford the titlecompound as colourless solid. Fraction I (114a, 0.90 g, 43% yield)..¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.87(d, J=1.0Hz, 1H), 7.64(d,J=9.5Hz, 1H), 7.20(dd, J=9.5,1.5Hz, 1H), 3.92(s,3H), 2.44(s,3H).Fraction II (114b, 0.80 g, 38% yield).. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): δ 7.72(d, J=1.3Hz, 1H), 7.65(d, J=8.8Hz, 1H), 7.20(dd,J=8.8,1.6Hz, 1H), 4.01(s,3H), 2.58(s,3H).

Intermediate 115:1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

To a solution of intermediate 114a (0.90 g, 4.00 mmoles) in Dioxan (14ml), bis(pinacaloto)diboron (1.1 g, 4.4 mmoles) and potassium acetate(0.785 g, 8.0 mmoles) were added and the system is degassed for 30 min.Bis(diphenylphosphinoferrocene)dichloro palladium.CH₂Cl₂ (0.163 g, 0.200mmoles) was added under nitrogen atmosphere and heated to 80° C. After12 h, the reaction mixture filtered through celite and concentrated. Thecrude product was purified by column chromatography with ethylacetate:petroleum ether to afford the title compound as off-white solid(0.85 g, 78% yield).). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ7.84(s,1H),7.65(d, J=8.0,0.7Hz, 1H), 7.53(d, J=8.1Hz,1H),4.03(s,3H),2.56(s,3H),1.38(s,12H).

Intermediate 116:2,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole

To a solution of intermediate 114b (0.80 g, 3.55 mmoles) in Dioxan (14ml), bis(pinacaloto)diboron (0.992 g, 3.90 mmoles) and potassium acetate(0.697 g, 7.10 mmoles) were added and the system is degassed for 30 min.Bis(diphenylphosphinoferrocene)dichloro palladium.CH₂Cl₂ (0.145 g, 0.177mmoles) was added under nitrogen atmosphere and heated to 80° C. After12 h, the reaction mixture filtered through celite and concentrated. Thecrude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.80 g,83% yield).). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.85(s,1H),7.62(dd,J=8.3,0.8Hz, 1H),7.19(d, J=8.4Hz, 1H),4.05(s,3H),2.58(s,3H),1.29(s,12H).

EXAMPLE 12-[(6-Amino-9H-purin-9-yl)methyl]-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of Adenine (0.685 g, 5.07 mmoles) in DMF (10 ml),potassium carbonate (0.701 g, 5.07 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 3 (1 g, 2.53 mmoles) was addedand stirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol: dichloromethane toafford the title compound as off-white solid (0.496 g, 43% yield). MP:207-209° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.11(d, J=2.4Hz, 1H),8.09(d, J=10.4 Hz, 2H), 7.92 (dd, J=9.0, 2.4 Hz, 1H), 7.48-7.39(m, 6H),7.21(s, 2H), 5.33(s, 2H). Mass: 448.20(M+).

EXAMPLE 2 6-Bromo-2-(morpholinomethyl)-3-phenyl-4H-chromen-4-one

To a solution of Intermediate 3 (0.30 g, 0.761 mmoles) in THF (2 ml),was added morpholine (0.066 g, 0.761 mmoles) at RT and refluxed for 12h. The reaction mixture was cooled, diluted with aqueous bicarbonatesolution and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.40 g,79% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.12(d, J=2.2Hz, 1H),7.98(dd, J=8.8,2.3 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.45-7.39(m, 3H),7.29(d, J=7.0Hz, 2H), 3.50(t, J=4.2Hz, 4H), 3.40(s, 2H), 2.32(br S, 4H).

EXAMPLE 2a 6-Bromo-2-(morpholinomethyl)-3-phenyl-4H-chromen-4-onehydrochloride

To a solution of Example 2 (0.10 g, 0.249 mmoles) in THF (2 ml), wasadded hydrochloric acid in diethyl ether (2 ml) at 0° C. and stirred for30 min. The precipitate formed was filtered, washed with pentane anddried to afford the title compound as pale yellow solid (0.110 g, 99%yield. MP: 229-230° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.13(s, 1H),8.06(d, J=8.7 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.48(m, 3H), 7.32(d,J=6.9Hz, 2H), 4.35(br s, 2H), 3.80(br s, 4H), 3.59(s, 2H), 3.25(br s,2H). Mass: 402.04(M⁺+1-HCl).

EXAMPLE 3 2-[(6-Amino-9H-purin-9-yl)methyl]-3-phenyl-4H-chromen-4-one

To a solution of Example 1 (0.1 g, 0.22 mmoles) in methanol (10 ml),palladium on carbon (10 mg) was added and the solution was hydrogenatedat RT under 5 kg/cm² pressure of hydrogen for 3 h. The solution wasfiltered through celite and concentrated. The crude product was purifiedby column chromatography with methanol: dichloromethane to afford thetitle compound as pale yellow solid (0.030 g, 37% yield). MP: 173-175°C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.10(d, J=12.5Hz, 1H), 8.05(d,J=8.0 Hz, 1H), 7.77 (t, J=7.7 Hz, 1H), 7.48-7.41(m, 6H), 7.22(s,2H),5.34(s, 2H). Mass: 370.05(M⁺+1).

EXAMPLE 4 2-(Morpholinomethyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 2 (0.1 g, 0.249 mmoles) in methanol (10 ml),palladium on carbon 20 mg) was added and the solution was hydrogenatedat RT under 5 kg/cm² pressure of hydrogen for 4 h. The solution wasfiltered through celite and concentrated. The crude product was purifiedby column chromatography with ethyl acetate: petroleum ether to affordthe title compound as brown solid (0.080 g, 87% yield). ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 8.08(d, J=7.8Hz, 1H), 7.90(t, J=7.4 Hz, 1H), 7.74(d, J=8.4 Hz, 1H), 7.55(t, J=7.4 Hz, 1H), 7.49(m, 3H), 7.31(d, J=6.5 Hz,2H), 3.72(br s,4H), 3.42(br s, 6H).

EXAMPLE 4a 2-(Morpholinomethyl)-3-phenyl-4H-chromen-4-one hydrochloride

To a solution of Example 4 (0.065 g, 0.202 mmoles) in THF (2 ml), wasadded hydrochloric acid in diethyl ether (2 ml) at 0° C. and stirred for30 min. The precipitate formed was filtered, washed with pentane anddried to afford the title compound as off-white solid (0.043 g, 60%yield. MP: 208-209° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 11.42(br s,1H), 8.08(d, J=7.8 Hz, 1H), 7.90 (t, J=8.1 Hz, 1H), 7.79(d, J=8.4Hz,1H), 7.55(t, J=7.5Hz,1H), 7.49-7.44(m,3H), 7.33(d, J=7.3Hz,2H), 4.24(brs, 2H), 3.81(br s, 5H), 3.08(br s, 3H). 322.10(M⁺+1-HCl).

EXAMPLE 52-[(1H-Benzo[d]imidazol-1-yl)methyl]-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of intermediate 3 (0.10 g, 0.258 mmoles) in THF (2 ml),was added benzimidazole (0.059 g, 0.507 mmoles) at RT and refluxed for 2h. The reaction mixture was cooled, diluted with aqueous bicarbonatesolution and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as pale yellow solid (0.040g, 40% yield). MP: 192-197° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.15(s, 1H), 8.10(d, J=2.3 Hz, 1H), 7.92 (dd, J=8.9, 2.3 Hz, 1H),7.63(m, 1H), 7.54(m, 4H), 7.41(d, J=6.8Hz, 2H), 7.18(m, 3H), 5.43(s,2H). 432.77(M⁺+1).

EXAMPLE 66-Bromo-2-[(4-methyl-1H-benzo[d]imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one

To a solution of intermediate 3 (0.10 g, 0.258 mmoles) in THF (2 ml),was added 4-methylbenzimidazole (0.066 g, 0.507 mmoles) at RT andrefluxed for 2 h. The reaction mixture was cooled, diluted with aqueousbicarbonate solution and extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated under reduced pressure.The crude product was purified by column chromatography with ethylacetate: petroleum ether to afford the title compound as pale yellowsolid (0.040 g, 35% yield). MP: 176-179° C. ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 8.10(s, 1H), 8.09(d, J=2.3 Hz, 1H), 7.92 (dd, J=9.0,2.5 Hz, 1H),7.55(m, 4H), 7.41(d, J=6.8Hz,2H), 7.08(t, J=7.5Hz, 1H),6.98(m,2H),5.43(s, 2H), 2.49(s,3H). Mass: 445.13(M+).

EXAMPLE 7 2-[(1H-benzo[d]imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one

To a solution of intermediate 5 (0.10 g, 0.317 mmoles) in dioxin (2 ml),was added benzimidazole (0.074 g, 0.634 mmoles) at RT and refluxed for12 h. The reaction mixture was cooled, diluted with aqueous bicarbonatesolution and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.050 g,44% yield). MP: 186-191° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.16(s,1H), 8.04(d, J=7.7 Hz, 1H), 7.78 (t, J=8.3Hz, 1H), 7.64(d, J=5.5Hz, 1H),7.54-7.42(m, 7H), 7.18(s, 3H), 5.43(s, 2H). Mass: 352.83(M⁺).

EXAMPLE 82-[(4-methyl-1H-benzo[d]imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one

To a solution of intermediate 5 (0.10 g, 0.317 mmoles) in dioxan (2 ml),was added 4-methylbenzimidazole (0.083 g, 0.634 mmoles) at RT andrefluxed for 12 h. The reaction mixture was cooled, diluted with aqueousbicarbonate solution and extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated under reduced pressure.The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.060 g,51% yield). MP: 204-208° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.11(s,1H), 8.04(d, J=7.6 Hz, 1H), 7.77 (t, J=7.6Hz, 1H), 7.55(m, 7H), 7.08(t,J=8.0Hz, 1H), 6.99(d, J=7.6Hz, 2H), 5.40(s, 2H), 2.48(s, 3H). Mass:367.25(M⁺+1).

EXAMPLE 9 2-[(6-Chloro-9H-purin-9-yl)methyl]-3-phenyl-4H-chromen-4-one

To a solution of 6-Chloropurine (0.146 g, 0.951 mmoles) in DMF (3 ml),potassium carbonate (0.131 g, 0.951 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 5 (0.150 g, 0.475 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as brownish yellow (0.053g, 28% yield). MP: 187-190° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.71(s, 1H), 8.67(s, 1H), 8.0 (d, J=7.0 Hz, 1H), 7.79 (dt, J=8.1, 1.5Hz,1H), 7.50(t, J=7.9Hz, 2H), 7.43(m, 5H), 5.53(s, 2H). 389.09(M⁺+1).

EXAMPLE 106-Bromo-2-[(6-chloro-9H-purin-9-yl)methyl]-3-phenyl-4H-chromen-4-one

To a solution of 6-Chloropurine (0.117 g, 0.761 mmoles) in DMF (3 ml),potassium carbonate (0.105 g, 0.761 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 3 (0.150 g, 0.380 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as brownish yellow (0.041g, 22% yield). MP: 234-236° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.71(s, 1H), 8.67(s, 1H), 8.11(d, J=2.4 Hz, 1H), 7.94 (d, J=9.0Hz, 1H),7.53 (d, J=8.8Hz, 1H), 7.41(m, 5H), 5.52(s, 2H). Mass: 466.79(M⁺−1).

EXAMPLE 11 2-((9H-Purin-6-ylthio)methyl)-3-phenyl-4H-chromen-4-one

To a solution of 6-Mercaptopurine (0.162 g, 0.951 mmoles) in DMF (3 ml),potassium carbonate (0.131 g, 0.951 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 5 (0.150 g, 0.475 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.061g, 33% yield). MP: 208-209° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ13.56(s, 1H), 8.52(s, 1H), 8.44(s, 1H), 8.05(d, J=7.9 Hz, 1H), 7.81 (t,J=7.2Hz, 1H), 7.58 (d, J=8.4Hz, 1H), 7.50(m 4H), 7.39(d, J=6.8Hz, 2H),4.62(s, 2H). Mass: 386.78(M⁺).

EXAMPLE 12 2-[(1H-Imidazol-1-yl)methyl]-3-phenyl-4H-chromen-4-one

To a solution of intermediate 5 (0.10 g, 0.317 mmoles) in dioxan (2 ml),was added imidazole (0.043 g, 0.634 mmoles) at RT and refluxed for 12 h.The reaction mixture was cooled, diluted with aqueous bicarbonatesolution and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as brownish yellow solid(0.040 g, 41% yield). MP: 168-171° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):δ 8.06(dd, J=7.9,1.3 Hz, 1H), 7.83 (dt, J=7.9, 1.5Hz, 1H), 7.61(s, 1H),7.58(d, J=8.5Hz, 1H), 7.51(m, 4H), 7.36(dd, J=8.0Hz, 2H), 7.12(s, 1H),6.90(s, 1H), 5.10(s, 2H). Mass: 303.29(M⁺+1).

EXAMPLE 132-[(9H-Purin-6-ylthio)methyl]-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of 6-Mercaptopurine (0.097 g, 0.570 mmoles) in DMF (5 ml),potassium carbonate (0.079 g, 0.570 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 3 (0.150 g, 0.380 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as grey solid (0.050 g, 28%yield). MP: 214-218° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 13.54(s,1H), 8.51(s, 1H), 8.43(s, 1H), 8.10(d, J=2.2 Hz, 1H), 7.95 (dd,J=8.9,2.3Hz, 1H), 7.59 (d, J=9.0Hz, 1H), 7.45(m 3H), 7.34(d, J=6.5Hz,2H), 4.62(s, 2H). Mass: 465.11 (M⁺).

EXAMPLE 142-((4-Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of 4-Aminopyrazalo[3,4-d]pyramiding (0.102 g, 0.761mmoles) in DMF (3 ml), potassium carbonate (0.105 g, 0.761 mmoles) wasadded and stirred at RT for 10 min. To this mixture intermediate 3(0.150 g, 0.380 mmoles) was added and stirred for 12 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as brownish yellow solid (0.031 g, 18% yield). MP: 236-240° C.¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.16(s, 1H), 8.11(s, 1H), 8.10(s,1H), 7.89(dd, J=8.8, 2.2Hz, 1H), 7.72 (br s, 2H), 7.40(m 6H), 5.41(s,2H). Mass: 449.78 (M⁺+1).

EXAMPLE 152-[(6-Amino-9H-purin-9-yl)methyl]-6-bromo-3-(4-fluorophenyl)-4H-chromen-4-one

To a solution of Adenine (0.0983 g, 0.727 mmoles) in DMF (5 ml),potassium carbonate (0.125 g, 0.727 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 8 (0.150 g, 0.364 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.030 g,18% yield). MP: 238-242° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.10(s,2H), 8.06(s, 1H), 7.93(dd, J=8.9,2.2 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H),7.45 (t, J=8.2 Hz, 2H), 7.29 (t, J=8.8 Hz, 2H), 7.22(s,2H), 5.34(s, 2H).Mass: 466.11(M+).

EXAMPLE 162-[(6-Amino-9H-purin-9-yl)methyl]-3-(4-fluorophenyl)-4H-chromen-4-one

To a solution of Adenine (0.121 g, 0.899 mmoles) in DMF (5 ml),potassium carbonate (0.155 g, 0.899 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 10 (0.150 g, 0.450 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.040 g,22% yield). MP: 212-216° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.11(s,2H), 8.07(s, 1H), 8.05(d, J=8.2 Hz, 1H), 7.78 (t, J=8.4 Hz, 1H), 7.50(m, 4H), 7.29(m, 4H), 5.34(s, 2H). Mass: 388.21(M+1).

EXAMPLE 176-Bromo-3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one

To a solution of intermediate 8 (0.150 g, 0.364 mmoles) in THF (5 ml),was added morpholine (0.0634 g, 0.728 mmoles) at RT and refluxed for 4h. The reaction mixture was cooled, diluted with aqueous bicarbonatesolution and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.50 g,32% yield). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.35(s, 1H), 7.81(d, J=7.7Hz, 1H), 7.39(m, 3H), 7.18(t, J=7.7 Hz, 2H), 3.80(br st, 6H), 2.64(br s,4H).

EXAMPLE 17a6-Bromo-3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-onehydrochloride

To a solution of Example 17 (0.050 g, 0.1192 mmoles) in THF (2 ml), wasadded hydrochloric acid in diethyl ether (2 ml) at 0° C. and stirred for30 min. The precipitate formed was filtered, washed with pentane anddried to afford the title compound as yellow solid (0.030 g, 55% yield.MP: 232-236° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.13(d, J=2.3 Hz,1H), 8.06 (d, J=8.9 Hz, 1H), 7.80(d, J=9.0Hz, 1H), 7.38(m,4H), 4.24(brs, 2H), 3.83(br s, 4H), 3.62(br s, 2H), 3.08(br s, 2H). Mass:419.75(M+1-HCl).

EXAMPLE 18 3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-one

To a solution of intermediate 10 (0.150 g, 0.450 mmoles) in dioxan (5ml), was added morpholine (0.0784 g, 0.90 mmoles) at RT and refluxed for12 h. The reaction mixture was cooled, diluted with aqueous bicarbonatesolution and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.80 g,52% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.06(dd, J=7.9.1.0 Hz,1H), 7.84(dt, J=8.3,1.2Hz, 1H), 7.7 (d, J=8.4 Hz, 1H), 7.51(t, J=7.6 Hz,1H), 7.36 (dt, J=6.0, 2.9 Hz, 2H), 7.28(t, J=8.9 Hz, 2H), 3.50(br s,4H), 3.39(br s, 2H), 2.49(br s, 4H).

EXAMPLE 18a 3-(4-fluorophenyl)-2-(morpholinomethyl)-4H-chromen-4-onehydrochloride

To a solution of Example 18 (0.080 g, 0.235 mmoles) in THF (2 ml), wasadded hydrochloric acid in diethyl ether (2 ml) at 0° C. and stirred for30 min. The precipitate formed was filtered, washed with pentane anddried to afford the title compound as yellow solid (0.080 g, 90% yield.MP: 225-229° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.08(d, J=6.6 Hz,1H), 7.95 (t, J=7.3 Hz, 1H), 7.78(d, J=8.2Hz, 1H), 7.55(t, J=7.6Hz, 1H),7.38(m,4H), 4.30(br s, 2H), 3.88(br s, 6H), 3.12(br s, 2H).). Mass:340.09(M+1-HCl).

EXAMPLE 192-[(6-Amino-9H-purin-9-yl)methyl]-6-bromo-3-o-tolyl-4H-chromen-4-one

To a solution of Adenine (0.099 g, 0.735 mmoles) in DMF (3 ml),potassium carbonate (0.101 g, 0.735 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 13 (0.150 g, 0.367 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.046 g,27% yield). MP: 252-255° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.11(d,J=2.3Hz, 1H), 8.03(s,1H), 7.97(s,1H), 7.94(dd, J=8.9,2.4 Hz, 1H), 7.54(d, J=8.8 Hz, 1H), 7.31-7.22 (m, 6H), 5.22(s, 2H), 2.00(s, 3H).). Mass:463.85(M+1).

EXAMPLE 207-[(6-Bromo-4-oxo-3-phenyl-4H-chromen-2-yl)methyl]-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione

To a solution of Theophylline (0.137 g, 0.761 mmoles) in DMF (3 ml),potassium carbonate (0.105 g, 0.761 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 3 (0.150 g, 0.380 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as brown solid (0.040 g,21% yield). MP: 253-255° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.11(d,J=2.4Hz, 1H), 8.03(s,1H), 7.94(dd, J=8.9,2.4 Hz, 1H), 7.52 (d, J=9.1 Hz,1H), 7.42 (m, 3H), 7.31 (d, J=6.6 Hz, 1H), 5.51(s, 2H), 3.13(s, 6H).).Mass: 492.69(M+).

EXAMPLE 212-(1-(6-Amino-9H-purin-9-yl)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of Adenine (0.266 g, 1.969 mmoles) in DMF (10 ml),potassium carbonate (0.272 g, 1.969 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 15 (0.400 g, 0.984 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.200g, 44% yield). MP: 230-231° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.45(s, 1H), 8.08(d, J=2.4Hz, 1H), 8.02(s,1H), 7.99(dd, J=8.9,2.4 Hz,1H), 7.68 (d, J=8.9 Hz, 1H), 7.47 (m, 3H), 7.35(d, J=6.5 Hz, 1H),7.20(s,2H), 5.69(q, J=7.2Hz, 1H),1.88(d, J=7.2Hz, 3H).). Mass: 463.92(M+1).

EXAMPLE 22 2-(1-(9H-Purin-6-ylthio)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of 6-Mercaptopurine (0.251 g, 1.477 mmoles) in DMF (10ml), potassium carbonate (0.255 g, 1.846 mmoles) was added and stirredat RT for 10 min. To this mixture intermediate 15 (0.300 g, 0.738mmoles) was added and stirred for 12 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light green solid (0.130g, 37% yield). MP: 234-237° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ13.54(s, 1H), 8.40(s, 1H), 8.37(s, 1H), 8.10(d, J=2.5Hz, 1H), 7.99(dd,J=8.8,2.5 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 7.39 (m, 4H), 7.26(s, 2H),5.47(q, J=7.2Hz, 1H),1.79(d, J=7.1Hz, 3H). Mass: 478.83(M⁺).

EXAMPLE 23 2-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of example 21 (0.080 g, 0.173 mmoles) in methanol (10 ml),palladium on carbon (10% 16 mg) was added and the solution washydrogenated at RT under 5 kg/cm² pressure of hydrogen for 24 h. Thesolution was filtered through celite and concentrated. The crude productwas purified by column chromatography with methanol: dichloromethane toafford the title compound as light yellow solid (0.025 g, 38% yield).MP: 254-257° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.46(s, 1H), 8.03(s,1H), 8.01(d, J=1.6Hz, 1H), 7.83(dt, J=7.3,1.7 Hz, 1H), 7.65 (d, J=8.2Hz, 1H), 7.50 (m, 4H), 7.37(dd, J=8.1,1.7 Hz, 1H),7.2 (s, 2H), 5.67(q,J=7.3Hz, 1H),1.89(d, J=7.2Hz, 3H).). Mass: 384.19(M+1).

EXAMPLE 24 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of intermediate 17 (0.20 g, 0.581 mmoles) in tert-butanol(6 ml), N,N-diisopropylethyl amine (0.2 ml, 1.162 mmoles) and6-bromopurine (0.087 g, 0.435 mmoles) were added and refluxed for 24 h.The reaction mixture was concentrated, diluted with water, extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as yellow solid (0.065 g, 24% yield). MP: 151-154° C. ¹H-NMR (δppm, DMSO-D₆, 400 MHz): δ 12.94(s, 1H), 8.09(br s, 3H), 7.94(d, J=7.9Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.42 (m, 6H), 5.22(br t, 1H), 1.82(d,J=6.4Hz, 3H). Mass: 463.99(M+1).

EXAMPLE 25 2((9H-purin-6-ylamino)methyl)-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of intermediate 19 (0.20 g, 0.605 mmoles) in tert-butanol(4 ml), N,N-diisopropylethylamine (0.2 ml, 1.211 mmoles) and6-bromopurine (0.096 g, 0.484 mmoles) were added and refluxed for 24 h.The reaction mixture was concentrated, diluted with water, extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as yellow solid (0.065 g, 24% yield). MP: 151-154° C. ¹H-NMR (δppm, DMSO-D₆, 400 MHz): δ 12.90(s, 1H), 8.20(ms, 4H), 7.91(dd, J=9.0,2.5 Hz, 1H), 7.49-7.35 (m, 6H), 4.64 (br s, 2H). Mass: 448.17(M+).

EXAMPLE 262-(1-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one

To a solution of 4-Aminopyrazalo[3,4-d]pyrimidine (0.299 g, 2.215mmoles) in DMF (10 ml), potassium carbonate (0.382 g, 2.769 mmoles) wasadded and stirred at RT for 10 min. To this mixture intermediate 15(0.450 g, 1.107 mmoles) was added and stirred for 12 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as light yellow solid (0.80 g, 16% yield). MP: 239-240° C.¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.10(d, J=2.5Hz, 1H), 8.09(s,1H),8.00(s, 1H), 7.97(dd, J=8.9,2.4 Hz, 1H), 7.69 (br s, 2H), 7.60(d, J=9.0Hz, 1H),7.31(br s, 3H), 7.12(br s, 2H), 5.83(q, J=7.1Hz, 1H),1.83(d,J=7.0Hz, 3H). Mass: 461.96(M+).

EXAMPLE 272-((6-Amino-9H-purin-9-yl)methyl)-6-methoxy-3-phenyl-4H-chromen-4-one

To a solution of adenine (0.234 g, 1.738 mmoles) in DMF (6 ml),potassium carbonate (0.240 g, 1.738 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 22 (0.300 g, 0.869 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as pale yellow solid (0.052g, 15% yield). MP: 197-198° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.08(s, 1H), 8.06(s, 1H), 7.47(m, 7H), 7.35(dd, J=9.0, 3.1 Hz, 1H), 7.19(s, 2H), 5.32(s, 2H), 3.83(s, 3H). Mass: 400.03(M⁺+1).

EXAMPLE 282-(1-(6-Amino-9H-purin-9-yl)ethyl)-6-bromo-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.190 g, 1.408 mmoles) in DMF (6 ml),potassium carbonate (0.194 g, 1.408 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 25 (0.300 g, 0.704 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light brown solidconsisting of a mixture of two atrop-isomers (0.082 g, 24% yield). MP:256-258° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ [8.47(s), 8.38(s), 1H],8.09(d, J=2.5 Hz, 1H), [8.05 (dd, J=9.0,3.0 Hz), 8.00(dd, J=9.0,2.5 Hz),1H], [8.01(s), 7.91(s), 1H], [7.81 (d, J=9.0 Hz), 7.69(d, J=8.9 Hz),1H], 7.50(m, 2H), 7.34(m, 2H), [7.22(s), 7.16(s), 2H], [5.71(q, J=7.0Hz), 5.64(q, J=7.2 Hz), 1H], 1.96 (d, J=7.2 Hz), 1.86(d, J=7.2 Hz), 3H].Mass: 481.73(M+1).

EXAMPLE 292-((6-Amino-9H-purin-9-yl)methyl)-6-bromo-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.131 g, 0.970 mmoles) in DMF (4 ml),potassium carbonate (0.133 g, 0.970 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 27 (0.200 g, 0.485 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.031 g,14% yield). MP: 231-233° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.11(d,J=2.5 Hz, 1H), 8.08(s, 1H), 8.04(s, 1H), 7.96(dd, J=8.9,2.5 Hz, 1H),7.54 (d, J=9.0 Hz, 1H), 7.49(d, J=3.5 Hz, 1H), 7.30(m, 4H), [5.42(d,J=16.5 Hz), 5.30(d, J=16.5 Hz) 2H]. Mass: 466.23(M+).

EXAMPLE 302-(1-(4-Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of 4-Aminopyrazalo[3,4-d]pyrimidine (0.279 g, 2.58 mmoles)in DMF (7 ml), potassium carbonate (0.357 g, 2.58 mmoles) was added andstirred at RT for 10 min. To this mixture intermediate 29 (0.340 g, 1.03mmoles) was added and stirred for 12 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid (0.80g, 16% yield). MP: 226-227° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.09(s,1H), 8.04(dd, J=7.9,1.5 Hz, 1H), 8.01(s, 1H), 7.82(dt, J=8.6,1.6Hz, 1H),7.58(d, J=8.4 Hz, 2H), 7.51(t, J=7.4Hz, 2H).7.31(br s, 3H),5.83(q, J=7.0Hz, 1H),1.84(d, J=7.0Hz, 3H). Mass: 383.40(M+).

EXAMPLE 31 2-(1-(6-Amino-9H-purin-9-yl)propyl)-3-phenyl-4H-chromen-4-one

To a solution of adenine (0.190 g, 1.408 mmoles) in DMF (6 ml),potassium carbonate (0.194 g, 1.408 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 32 (0.300 g, 0.704 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.082 g, 24% yield). MP: 223-225° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):δ 8.54(s, 1H), 8.04(s, 1H), 8.03(dd, J=7.9,1.5 Hz, 1H), 7.86(dt,J=7.1,1.6 Hz), 7.78(d, J=7.9 Hz, 1H), 7.51(m, 4H), 7.33(dd, J=7.8,1.6Hz, 2H), 7.23(s, 2H), 5.52(t, J=7.3 Hz, 1H), 2.49 (m, 2H), 0.74(t, J=7.3Hz, 3H). Mass: 398.12(M+1).

EXAMPLE 322-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.233 g, 1.728 mmoles) in DMF (6 ml),potassium carbonate (0.238 g, 1.728 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 36 (0.300 g, 0.864 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.200g, 57% yield). MP: 155-158° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.46(s,1H), 8.02(s,1H), 8.02(dd, J=7.7,1.4 Hz, 1H), 7.84 (dt, J=8.6,1.5Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.51(m, 2H), 7.27-7.19(m, 5H), 5.70(q,J=7.2 Hz, 1H), 1.90 (d, J=7.2 Hz,3H). Mass: 402.25(M+1).

EXAMPLE 332-((6-Amino-9H-purin-9-yl)methyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.227 g, 1.68 mmoles) in DMF (5 ml), potassiumcarbonate (0.232 g, 1.68 mmoles) was added and stirred at RT for 10 min.To this mixture intermediate 38 (0.280 g, 0.840 mmoles) was added andstirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol: dichloromethane toafford the title compound as brown solid (0.046 g, 13% yield). MP:202-205° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.08(s,1H), 8.04(s,1H),8.05(dd, J=5.0,1.8 Hz, 1H), 7.81 (dt, J=8.5,1.7 Hz, 1H), 7.53-7.441(m,4H), 7.30(d, J=6.6 Hz,1H), 7.26(d, J=6.6Hz,1H), 7.22(s,2H), [5.43(d,J=16.4 Hz), 5.30(d, J=16.4 Hz),2H]. Mass: 387.83(M+).

EXAMPLE 342-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.179 g, 1.32 mmoles) in DMF (5 ml), potassiumcarbonate (0.183 g, 1.68 mmoles) was added and stirred at RT for 10 min.To this mixture intermediate 40 (0.230 g, 0.662 mmoles) was added andstirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol: dichloromethane toafford the title compound as brown solid (0.080 g, 30% yield). MP:247-250° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ [8.48(s),8.39(s), 1H],[8.05(s), 7.91(s), 1H], 8.03(d, J=7.8 Hz, 1H), 7.86 (m, 2H), 7.53(m,3H), 7.36-7.18(m, 4H), 5.68(q, J=7.3Hz, 1H), [1.97(d, J=7.2 Hz), 1.87(d,J=7.1 Hz), 3H]. Mass: 402.32(M+1).

EXAMPLE 352-(1-(6-Amino-9H-purin-9-yl)propyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.524 g, 3.87 mmoles) in DMF (5 ml), potassiumcarbonate (0.535 g, 3.87 mmoles) was added and stirred at RT for 10 min.To this mixture intermediate 43 (0.700 g, 1.93 mmoles) was added andstirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol: dichloromethane toafford the title compound as brown solid (0.060 g, 7% yield). MP:160-163° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ [8.57(s),8.45(s), 1H],[8.08(s), 7.92(s), 1H], 8.03(d, J=8.0 Hz, 1H), 7.89 (m, 2H), 7.54(m,3H), 7.35-7.17(m, 4H), [5.48(t, J=7.9Hz), 5.46(t, J=7.0Hz), 1H], 2.48(m,2H), [0.82(t, J=7.4 Hz), 0.75(t, J=7.3 Hz), 3H]. Mass: 416.04(M+1).

EXAMPLE 362-(1-(6-amino-9H-purin-9-yl)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.404 g, 2.99 mmoles) in DMF (12 ml),potassium carbonate (0.413 g, 2.99 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 46 (0.540 g, 1.49 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as brownish yellow solid(0.115 g, 19% yield). MP: 102-107° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):δ 8.54(s,1H), 8.03(s, 1H), 8.01(d, J=10.1 Hz, 1H), 7.87 (t, J=8.4Hz,1H), 7.79 (d, J=8.4Hz, 1H), 7.52 (t, J=7.6Hz, 2H), 7.28(m, 3H), 7.18 (d,J=7.4Hz, 2H), 5.51(t, J=7.9Hz, 1H), 2.39(m, 2H), 0.76(t, J=7.3 Hz, 3H).Mass: 415.97(M+).

EXAMPLE 372-(1-(6-Amino-9H-purin-9-yl)propyl)-3-(4-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.389 g, 2.87 mmoles) in DMF (12 ml),potassium carbonate (0.497 g, 2.87 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 49 (0.520 g, 1.43 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid (0.55g, 9% yield). MP: 223-227° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.54(s,1H), 8.05(s, 1H), 8.03(dd, J=8.0,1.6 Hz, 1H), 7.86 (dt,J=7.1,1.6Hz, 1H), 7.78 (d, J=7.8Hz, 1H), 7.51 (dt, J=8.0,1.1Hz, 1H),7.38(t, J=8.1Hz, 2H), 7.30 (t, J=8.8Hz, 2H), 7.23(s,2H), 5.50(t,J=7.7Hz, 1H), 2.39(m, 2H), 0.76(t, J=7.3 Hz, 3H). Mass: 416.11(M+1).

EXAMPLE 382-(1-(6-amino-9H-purin-9-yl)propyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of adenine (0.374 g, 2.76 mmoles) in DMF (10 ml),potassium carbonate (0.382 g, 2.76 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 52 (0.500 g, 1.38 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.110 g, 19% yield). MP: 266-272° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):δ 8.54(s,1H), 8.04(s, 1H), 7.92(dd, J=9.3,4.3 Hz, 1H), 7.78 (dt,J=8.6,3.2 Hz, 1H), 7.70 (dd, J=8.3,5.3 Hz, 1H), 7.46 (m, 3H), 7.32(d,J=6.4Hz, 2H), 7.21(s,2H), 5.53(t, J=7.7Hz, 1H), 2.39(m, 2H), 0.74(t,J=7.3 Hz, 3H). Mass: 416.11(M+1).

EXAMPLE 392-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-(4-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.412 g, 3.05 mmoles) in DMF (10 ml),potassium carbonate (0.527 g, 3.81 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 55 (0.530 g, 1.52 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.050 g, 8% yield). MP: 210-212° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.46(s,1H), 8.03(s, 1H), 8.02(dd, J=8.1,1.5 Hz, 1H), 7.83 (dt, J=7.1,1.5Hz, 1H), 7.67 (d, J=8.3Hz, 1H), 7.50(t, J=7.7Hz, 1H), 7.41(d, J=8.6Hz,1H),7.39(d, J=8.4Hz, 1H),7.30(t, J=8.9Hz, 2H),7.23(s,1H), 5.68(q,J=6.9Hz, 1H), 1.90(d, J=7.2 Hz, 3H). Mass: 402.32(M+1).

EXAMPLE 402-(1-(6-Amino-9H-purin-9-yl)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of adenine (0.389 g, 2.88 mmoles) in DMF (12 ml),potassium carbonate (0.398 g, 2.88 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 57 (0.500 g, 1.44 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.210 g, 36% yield). MP: 264-269° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):δ 8.46(s,1H), 8.02(s, 1H), 7.80(dd, J=9.1,4.4 Hz, 1H), 7.74 (m, 2H),7.48 (m, 3H), 7.36(dd, J=8.0,1.7Hz,2H), 7.21(s,1H), 5.68(q, J=7.2Hz,1H), 1.88(d, J=7.2 Hz, 3H). Mass: 402.11(M+1).

EXAMPLE 412-(1-(4-Amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 58 (0.498 g, 2.06 mmoles) in DMF (5 ml),potassium carbonate (0.356 g, 2.50 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 29 (0.340 g, 1.03 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.160 g, 32% yield). MP: 176-178° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):δ 8.09(s,1H), 8.04(d, J=8.0 Hz, 1H), 7.83(t, J=7.0 Hz, 1H), 7.63(d,J=6.5 Hz, 2H), 7.51 (t, J=7.3 Hz, 1H), 7.46(t, J=8.1 Hz, 1H), 7.33 (m,3H), 7.12(m, 4H), 7.06(dd, J=8.2,2.3 Hz, 1H), 5.98(q, J=6.7Hz, 1H),3.81(s, 3H), 1.90(d, J=7.0 Hz, 3H). Mass: 490.10(M+1).

EXAMPLE 422-(1-(4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of example 41 (0.130 g, 0.265 mmoles) in dichloromethane(26 ml), BBr₃ (1M in dichloromethane, 2.6 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure to afford the title compound aslight yellow solid (0.070 g, 56% yield). MP: 212-216° C. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 9.78(s,1H), 8.24(d, J=7.5 Hz, 1H), 8.05(d, J=7.9Hz, 1H), 7.85(t, J=8.4 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.53(t, J=7.7Hz, 1H), 7.36-7.02 (m, 9H), 6.90(d, J=8.2Hz, 1H), 6.03(q, J=6.9Hz, 1H),1.91(d, J=7.3 Hz, 3H). Mass: 476.17(M+1).

EXAMPLE 43 2-((9H-purin-6-ylamino) methyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 59 (1.50 g, 7.06 mmoles) indichloromethane (15 ml), triethylamine (2.9 ml, 21.20 mmoles) was addedfollowed by N-Boc-Glycine (1.3 g, 7.77 mmoles). To this mixture HATU(5.3 g, 14.13 mmoles) was added and stirred at RT for 12 h. The reactionmixture was quenched by the addition of water and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with ethyl acetate: petroleum ether to afford theisoflavone intermediate (1.12 g). To a solution of this intermediate(0.60 g) in dichloromethane (10 ml), trifluoroacetic acid (2.5 ml) wasadded and stirred at RT for 2 h. The reaction mixture was concentrated,basified with sodium bicarbonate solution, extracted with ethyl acetate.The organic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the amine intermediate (0.38 g). To asolution of this amine intermediate (0.37 g, 1.47 mmoles) intert-butanol (6 ml), N,N-diisopropylethylamine (0.5 ml, 2.94 mmoles) and6-chloropurine (0.226 g, 1.47 mmoles) were added and refluxed for 24 h.The reaction mixture was concentrated, diluted with water, extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as brown solid (0.131 g, 24% yield). MP: 155-158° C. ¹H-NMR (δppm, DMSO-D₆, 400 MHz): δ 12.96(s, 1H), 8.14-8.040(m, 4H), 7.77(t, J=8.2Hz, 1H), 7.48-7.36 (m, 7H), 4.60 (br s, 2H). Mass: 369.91 (M⁺).

EXAMPLE 44 2-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-o-tolyl-4H-chromen-4-one

To a solution of intermediate 61 (0.610 g, 2.30 mmoles) in acetic acid(8 ml) bromine (0.23 ml, 4.61 mmoles) was added at 0° C. The reactionmixture heated to 60° C. After 6 h, the reaction mixture was cooled toRT, quenched by the addition of water. The precipitate formed wasfiltered and dried under reduced pressure to afford the bromointermediate (0.700 g). This intermediate (0.650 g, 1.88 mmoles) wasadded to a solution of adenine (0.510 g, 3.77 mmoles) and potassiumcarbonate (0.521 g, 3.77 mmoles) in DMF (15 ml). After 12 h, thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as light brown solid as a atrope isomers (0.030 g, 4% yield).MP: 202-205° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.42(d, J=3.5 Hz,1H), [8.07(s), 7.95(s), 1H], 8.04(t, J=5.6 Hz, 1H), 7.84(q, J=7.2 Hz,1H), [7.70 (d, J=8.2 Hz), 7.68 (d, J=8.1 Hz), 1H], 7.51(t, J=7.6 Hz,1H), 7.35-7.20 (m, 6H), 5.56(m, 1H), [2.09(s), 1.90(s), 3H], [1.95(d,J=7.1 Hz), 1.84 d, J=7.3 Hz), 3H]. Mass: 397.77(M⁺).

EXAMPLE 45 2-((9H-purin-6-ylamino)methyl)-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 64 (0.330 g, 1.22 mmoles) in tert-butanol(4 ml), N,N-diisopropylethylamine (0.42 ml, 2.45 mmoles) and6-bromopurine (0.195 g, 0.980 mmoles) were added and refluxed for 24 h.The reaction mixture was concentrated, diluted with water, extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as yellow solid (0.040 g, 8% yield). MP: 143-147° C. ¹H-NMR (δppm, DMSO-D₆, 400 MHz): δ 12.90(s,1H), 8.20(br s, 1H), 8.10(s,1H),8.09(s, 1H), 8.05(dd, J=7.9,1.4 Hz, 1H), 7.79(dt, J=8.6,1.5 Hz, 1H),7.51-7.41 (m, 4H), 7.28(m,2H), 4.64 (br s, 2H). Mass: 387.90(M⁺).

EXAMPLE 46 2-((9H-purin-6-ylamino)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 65 (1.50 g, 6.51 mmoles) indichloromethane (15 ml), triethylamine (2.7 ml, 19.54 mmoles) was addedfollowed by N-Boc-Glycine (1.3 g, 7.81 mmoles). To this mixture HATU(4.9 g, 13.03 mmoles) was added and stirred at RT for 12 h. The reactionmixture was quenched by the addition of water and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with ethyl acetate: petroleum ether to afford theisoflavone intermediate (0.80 g). To a solution of this intermediate(0.80 g) in dichloromethane (10 ml), trifluoroacetic acid (1.5 ml) wasadded and stirred at RT for 2 h. The reaction mixture was concentrated,basified with sodium bicarbonate solution, extracted with ethyl acetate.The organic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the amine intermediate (0.471 g). To asolution of this amine intermediate (0.30 g, 1.14 mmoles) intert-butanol (6 ml), N,N-diisopropylethylamine (0.5 ml, 2.94 mmoles) and6-bromopurine (0.177 g, 0.891 mmoles) were added and refluxed for 24 h.The reaction mixture was concentrated, diluted with water, extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as brown solid (0.235 g, 55% yield). MP: 211-214° C. ¹H-NMR (δppm, DMSO-D₆, 400 MHz): δ 12.97(s,1H), 8.20(br s, 1H), 8.14(s, 1H),8.11(s, 1H), 8.06(dd, J=7.9,1.4 Hz, 1H), 7.78(dt J=8.4,1.3 Hz, 1H), 7.49(m, 3H), 7.27-7.17(m, 3H), 4.10(q, J=5.3Hz, 1H), 3.16(d, J=5.0Hz,2H).Mass: 387.90(M⁺).

EXAMPLE 47 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 65 (2.0 g, 8.68 mmoles) in dichloromethane(20 ml), triethylamine (3.6 ml, 26.06 mmoles) was added followed byN-Boc-Alanine (1.97 g, 10.42 mmoles). To this mixture HATU (6.6 g, 17.37mmoles) was added and stirred at RT for 12 h. The reaction mixture wasquenched by the addition of water and extracted with dichloromethane.The organic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with ethyl acetate: petroleum ether to afford theisoflavone intermediate (1.70 g). To a solution of this intermediate(1.7 g) in dichloromethane (20 ml), trifluoroacetic acid (3 ml) wasadded and stirred at RT for 2 h. The reaction mixture was concentrated,basified with sodium bicarbonate solution, extracted with ethyl acetate.The organic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the amine intermediate (0.641 g). To asolution of this amine intermediate (0.30 g, 1.05 mmoles) intert-butanol (6 ml), N,N-diisopropylethylamine (0.36 ml, 2.17 mmoles)and 6-bromopurine (0.168 g, 0.847 mmoles) were added and refluxed for 24h. The reaction mixture was concentrated, diluted with water, extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as off-white solid (0.041 g, 10% yield). MP: 135-138° C. ¹H-NMR(δ ppm, DMSO-D₆, 400 MHz): δ 12.95(s,1H), 8.15(t, J=6.8Hz, 1H), 8.11(s,1H), 8.08(s, 1H), 8.03(d, J=7.8 Hz, 1H), 7.81(t, J=7.3Hz, 1H), 7.60 (d,J=8.3Hz, 1H), 7.49 (t, J=7.3Hz, 2H), 7.25(m,3H), 5.19(br m, 1H), 1.56(d,J=6.9Hz,3H). Mass: 402.18(M⁺+1).

EXAMPLE 482-(1-(6-amino-9H-purin-9-yl)ethyl)-6-fluoro-3-(2-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.443 g, 3.28 mmoles) in DMF (10 ml),potassium carbonate (0.453 g, 3.28 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 68 (0.600 g, 1.64 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solidconsisting of a mixture of two atrop-isomers (0.082 g, 24% yield). MP:245-248° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ [8.49(s), 8.39(s), 1H],[8.05 (s), 7.91(s), 1H], 7.92(m, 1H), 7.81(m, 2H), 7.52(m, 2H), 7.36(m,4H), [5.69(q, J=7.2Hz), 5.64(q, J=7.2 Hz), 1H], 1.96 (d, J=7.1 Hz),1.86(d, J=7.2 Hz), 3H]. Mass: 419.82(M⁺).

EXAMPLE 492-(1-(6-Amino-9H-purin-9-yl)ethyl)-3-(3,5-difluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.370 g, 2.73 mmoles) in DMF (8 ml), potassiumcarbonate (0.378 g, 2.73 mmoles) was added and stirred at RT for 10 min.To this mixture intermediate 72 (0.500 g, 1.36 mmoles) was added andstirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol: dichloromethane toafford the title compound as light brown solid (0.121 g, 21% yield). MP:267-269° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.45 (s, 1H), 8.02(s,1H), 8.01(d, J=5.9Hz,1H), 7.85(t, J=8.5Hz,1H), 7.70(d, J=8.4 Hz, 1H),7.52(t, J=7.7 Hz, 1H), 7.30(t, J=9.4 Hz, 1H), 7.23(s,2H), 7.11(d, J=7.6Hz, 2H), 5.70 (q, J=7.2 Hz, 1H), 1.91(d, J=7.1 Hz, 3H). Mass:419.82(M⁺).

EXAMPLE 502-(1-(6-amino-9H-purin-9-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of adenine (0.370 g, 2.73 mmoles) in DMF (8 ml), potassiumcarbonate (0.378 g, 2.73 mmoles) was added and stirred at RT for 10 min.To this mixture intermediate 75 (0.500 g, 1.36 mmoles) was added andstirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol: dichloromethane toafford the title compound as light brown solid (0.150 g, 26% yield). MP:252-255° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.46 (s, 1H), 8.02(s,1H), 7.82(dd, J=9.2,4.4Hz,1H), 7.76(dd, J=8.0,3.0Hz,1H), 7.72(td,J=6.8,3.6Hz, 1H), 7.51(q, J=7.8 Hz, 1H), 7.28-7.18(m, 5H), 5.70 (q,J=7.0Hz, 1H), 1.89(d, J=7.2 Hz, 3H). Mass: 420.03(M⁺+1).

EXAMPLE 512-(1-(4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 58 (0.484 g, 2.01 mmoles) in DMF (6 ml),potassium carbonate (0.345 g, 2.50 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 36 (0.350 g, 1.00 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.302 g, 59% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.07(s,1H),8.04(dd, J=7.9,1.4 Hz, 1H), 8.02(dt, J=6.9,1.4 Hz, 1H), 7.67(d, J=8.4Hz, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.46(t, J=7.9 Hz, 1H), 7.31 (br s, 1H),7.19(d, J=7.7 Hz, 1H), 7.10(t, J=2.1 Hz, 1H), 7.07(dt, J=8.6,4.0 Hz,2H), 6.90(br s, 2H), 6.05(q, J=6.9Hz, 1H), 3.80(s, 3H), 1.90(d, J=7.1Hz, 3H).

EXAMPLE 51a2-(1-(4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 51 (0.150 g, 0.290 mmoles) in dichloromethane(25 ml), BBr₃ (1M in dichloromethane, 1.5 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as greycolour solid (0.110 g, 75% yield). MP: 282-285° C. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 9.69(s,1H), 8.06(s, 1H), 8.05(dd, J=8.0, 1.6 Hz,1H), 7.86(dt, J=7.2,1.6 Hz, 1H), 7.68(t, J=8.2 Hz, 1H), 7.53 (dt,J=8.0,0.9 Hz, 1H), 7.34(t, J=8.0 Hz, 1H), 7.29 (br s, 1H), 7.06-6.84(m,6H), 6.03(q, J=7.1 Hz, 1H), 1.89(d, J=7.1 Hz, 3H). Mass: 493.95(M⁺).

EXAMPLE 522-((4-Amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 58 (0.765 g, 3.17 mmoles) in DMF (7 ml),potassium carbonate (0.548 g, 3.96 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 5 (0.500 g, 1.58 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.280 g, 37% yield). MP: 111-115° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):δ 8.23(s,1H), 8.05(dd, J=8.0,1.4 Hz, 1H), 7.77(dt, J=8.5,1.5 Hz, 1H),7.49-7.31(m, 8H), 7.20 (d, J=7.6 Hz, 1H), 7.12(s, 1H), 7.04(dd,J=8.0,2.1 Hz, 1H), 5.51(s, 2H), 3.80(s, 3H). Mass: 475.89(M⁺).

EXAMPLE 532-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of example 52 (0.150 g, 0.315 mmoles) in dichloromethane(30 ml), BBr₃ (1M in dichloromethane, 1.5 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as lightyellow solid (0.040 g, 27% yield). MP: 154-158° C. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 9.69(s,1H), 8.22(s,1H), 8.06(dd, J=7.8,1.2 Hz, 1H),7.49(t, J=7.3 Hz, 1H), 7.44(d, J=8.5 Hz, 1H), 7.37-7.29(m, 6H), 7.03 (d,J=7.9Hz, 2H), 6.86(dd, J=8.3,1.6 Hz, 1H), 5.49(s, 2H). Mass:462.03(M⁺+1).

EXAMPLE 542-((4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 58 (0.278 g, 1.15 mmoles) in DMF (6 ml),potassium carbonate (0.363 g, 2.62 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 77 (0.350 g, 1.05 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light brown solid (0.220g, 40% yield). MP: 175-178° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.21(s,1H), 8.05(dd, J=8.0,1.7 Hz, 1H), 7.80(m,1H), 7.51(m, 2H), 7.45(t,J=8.0 Hz, 1H), 7.39(m, 1H), 7.18-7.08(m,5H), 7.04 (dd, J=8.3,2.0 Hz,1H), 5.54(s, 2H), 3.80(s, 3H). Mass: 493.81(M⁺).

EXAMPLE 552-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of example 54 (0.200 g, 0.383 mmoles) in dichloromethane(30 ml), BBr₃ (1M in dichloromethane, 2.0 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as off-whitesolid (0.070 g, 36% yield). MP: 280-283° C. ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 9.69(s,1H), 8.20(s,1H), 8.06(dd, J=8.2,1.7 Hz, 1H), 7.80(m,1H),7.51(m 2H), 7.39(m,2H), 7.17(m, 2H), 7.11(dt, J=8.7,2.2 Hz, 1H), 7.02(d,J=8.6 Hz, 1H), 7.00(s,1H), 6.86 (dd, J=7.7,1.8Hz, 1H), 5.5 (s, 2H).Mass: 479.88(M⁺).

EXAMPLE 56 (R)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 65 (1.00 g, 4.34 mmoles) indichloromethane (15 ml), triethylamine (1.8 ml, 13.02 mmoles) was addedfollowed by N-Boc-D-Alanine (0.986 g, 5.21 mmoles). To this mixture HATU(3.3 g, 8.68 mmoles) was added and stirred at RT for 12 h. The reactionmixture was quenched by the addition of water and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with ethyl acetate: petroleum ether to afford theisoflavone intermediate (1.70 g). To a solution of this intermediate(0.8 g) in dichloromethane (10 ml), trifluoroacetic acid (3 ml) wasadded and stirred at RT for 2 h. The reaction mixture was concentrated,basified with sodium bicarbonate solution, extracted with ethyl acetate.The organic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the amine intermediate (0.410 g). To asolution of this amine intermediate (0.41 g, 1.52 mmoles) intert-butanol (7 ml), N,N-diisopropylethylamine (0.53 ml, 3.04 mmoles)and 6-bromopurine (0.242 g, 1.21 mmoles) were added and refluxed for 24h. The reaction mixture was concentrated, diluted with water, extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as off-white solid (0.130 g, 21% yield). MP: 274-276° C. ¹H-NMR(δ ppm, DMSO-D₆, 400 MHz): δ 12.96(s,1H), 8.14-8.01(m, 4H), 8.11(s, 1H),7.81(dt, J=8.5,1.5 Hz, 1H), 7.60(d, J=8.4Hz, 1H), 7.49 (m, 2H),7.25-7.19 (m, 3H), 5.18(br m, 1H), 1.56(d, J=7.0Hz,3H). Mass:402.04(M⁺+1).

EXAMPLE 57 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of intermediate 50 (2.50 g, 10.85 mmoles) indichloromethane (25 ml), triethylamine (4.5 ml, 32.57 mmoles) was addedfollowed by N-Boc-L-Alanine (2.46 g, 13.03 mmoles). To this mixture HATU(8.25 g, 21.71 mmoles) was added and stirred at RT for 12 h. Thereaction mixture was quenched by the addition of water and extractedwith dichloromethane. The organic layer was dried over sodium sulphateand concentrated under reduced pressure. The crude product was purifiedby column chromatography with ethyl acetate: petroleum ether to affordthe isoflavone intermediate (1.45 g). To a solution of this intermediate(1.40 g) in dichloromethane (20 ml), trifluoroacetic acid (1.4 ml) wasadded and stirred at RT for 2 h. The reaction mixture was concentrated,basified with sodium bicarbonate solution, extracted with ethyl acetate.The organic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the amine intermediate (0.850 g). To asolution of this amine intermediate (0.450 g, 1.52 mmoles) intert-butanol (7 ml), N,N-diisopropylethylamine (0.55 ml, 3.17 mmoles)and 6-chloropurine (0.194 g, 1.27 mmoles) were added and refluxed for 24h. The reaction mixture was concentrated, diluted with water, extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as yellow solid (0.100 g, 15% yield). MP: 196-198° C. ¹H-NMR (δppm, DMSO-D₆, 400 MHz): δ 12.95(s, 1H), 8.11-(m, 3H), 7.69 (m, 3H), 7.42(m, 5H), 5.20(br m, 1H), 1.54(d, J=6.7Hz, 3H). Mass: 402.18(M⁺+1).

EXAMPLE 57a2-((4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.404 g,5.36 mmoles) in DMF (28 ml), potassium carbonate (1.85 g, 13.4 mmoles)was added and stirred at RT for 10 min. To this mixture, intermediate 5(2.11 g, 6.70 mmoles) was added and stirred for 12 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as light yellow solid (1.10 g, 41% yield). ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 8.18(s, 1H), 8.06(dd, J=8.0, 1.6 Hz, 1H), 7.77(m,1H), 7.50 (dt, J=8.0, 0.9 Hz, 1H), 7.41-7.30(m, 6H), 5.44(s, 2H).

EXAMPLE 57b2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6.0 g, 23mmoles) in DMF (110 ml), potassium carbonate (7.94 g, 57.2 mmoles) wasadded and stirred at RT for 10 min. To this mixture, intermediate 29(9.5 g, 28.76 mmoles) was added and stirred for 12 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as light yellow solid (2.0 g, 17% yield). ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 8.12(dd, J=7.9,1.6Hz, 1H), 8.10(s,1H), 7.91(m, 1H),7.68 (d, J=8.2 Hz, 1H), 7.60(dt, J=7.9,0.9Hz, 1H), 7.36(m, 3H),7.18(m,2H), 5.93(q, J=7.1 Hz, 1H), 1.91(d, J=7.1Hz, 3H).

EXAMPLE 57c2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.30 g,5.299 mmoles) in DMF (23 ml), potassium carbonate (1.80 g, 13.24 mmoles)was added and stirred at RT for 10 min. To this mixture, intermediate 36(2.3 g, 6.62 mmoles) was added and stirred for 12 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as light yellow solid (0.800 g, 24% yield). ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 8.04(d, J=1.6Hz, 1H), 8.02(s,1H), 7.94 (s, 1H),7.86 (dt, J=8.0,1.5 Hz, 1H), 7.66(d, J=8.4Hz, 1H), 7.53(t, J=7.5Hz, 1H),7.29(m, 1H), 7.09(dt, J=7.7,2.4Hz, 1H), 6.88(m,1H), 5.93(q, J=7.0Hz,1H), 1.83(d, J=7.1Hz, 3H).

Example 57d2-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 3.01mmoles) in DMF (5 ml), N,N-Diisopropylethylamine (0.5 ml, 6.02 mmoles)was added and stirred at RT for 10 min. To this mixture, intermediate 90(1.3 g, 5.11 mmoles) was added and stirred for 16 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as light yellow solid (0.351 g, 23% yield). ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 8.17(s, 1H), 7.76-7.63(m, 2H), 7.55 (dd, J=9.1, 4.2Hz, 1H), 7.39-7.28(m, 5H), 5.44(s, 2H).

EXAMPLE 57e2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (12.8 g,49.03 mmoles) in DMF (50 ml), cesium carbonate (18.7 g, 57.62 mmoles)was added and stirred at RT for 10 min. To this mixture, intermediate 57(10 g, 28.81 mmoles) was added and stirred for 17 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as light yellow solid (3.8 g, 25% yield). ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 8.02(s, 1H), 7.72(m, 3H), 7.28(m, 3H), 7.09(br s,2H), 5.86 (q, J=7.1Hz, 1H), 1.82(d, J=7.0Hz, 3H).

EXAMPLE 57f2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10.9 g,41.90 mmoles) in DMF (45 ml), cesium carbonate (16.0 g, 49.30 mmoles)was added and stirred at RT for 10 min. To this mixture, intermediate 75(9.0 g, 24.65 mmoles) was added and stirred for 17 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as light yellow solid (3.2 g, 24% yield). ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 8.01(s, 1H), 7.81-7.69(m, 3H), 7.28(s, 1H), 7.08(dt, J=8.5, 1.8Hz, 1H), 6.88(br s, 2H), 5.93 (q, J=7.0Hz, 1H) 1.83(d,J=7.0Hz, 3H).

EXAMPLE 57g 2-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.44 g,5.52 mmoles) in DMF (20 ml), potassium carbonate (0.763 g, 5.52 mmoles)was added and stirred at RT for 10 min. To this mixture, intermediate 46(1.0 g, 2.76 mmoles) was added and stirred for 17 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as light yellow solid (0.440 g, 29% yield). ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 8.04(dd, J=7.9,1.4Hz, 1H), 8.01(s,1H), 7.87(m,1H)7.68 (d, J=8.5Hz, 1H), 7.53(t, J=7.2Hz, 1H), 7.29(br s, 1H), 7.09(dt,J=8.9,1.6Hz, 1H), 6.88(m,2H),5.72 (, J=7.5Hz, 1H), 2.42(quintet,J=7.4Hz,2H), 0.75(t, J=7.3Hz, 3H).

EXAMPLE 582-((4-amino-3-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57a (0.250 g, 0.50 mmoles) in DMF (5 ml),ethanol (2.5 ml) and water (2.5 ml), 3-pyridinylboronic acid (0.080 g,0.65 mmoles) and sodium carbonate (0.264 g, 2.5 mmoles) were added andthe system is degassed for 30 min Tetrakis triphenylphosphine Palladium(0.109 g, 0.095 mmoles) was added under nitrogen atmosphere and heatedto 80° C. After 12 h, the reaction mixture was celite filtered,concentrated and extracted with ethyl acetate. The organic layer wasdried over sodium sulphate and concentrated under reduced pressure. Thecrude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.030 g,13% yield). MP: 253-255° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.78(d,J=1.7Hz, 1H), 8.65(dd, J=4.7,1.3Hz, 1H), 8.24(s,1H), 8.05(dd,J=7.9,1.6Hz, 1H), 8.00(td, J=7.9,1.9 Hz, 1H), 7.77(d, J=7.2,1.7 Hz, 1H),7.54-7.43(m, 3H), 7.37-7.30(m,5H), 7.12(br s, 2H), 5.54(s,2H). Mass:447.19(M⁺+1).

EXAMPLE 592-((4-amino-3-(3-hydroxyprop-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57a (0.180 g, 0.363 mmoles) in THF (5 ml),propargyl alcohol (0.051 g, 0.436 mmoles) diisopropylamine (0.31 ml,1.81 mmoles), copper(I) iodide (7 mg, 0.036 mmoles) and) Tetrakistriphenylphosphine Palladium (0.042 g, 0.0363 mmoles) were added and thesystem is degassed for 30 min and heated to reflux for 4 h. The reactionmixture filtered through celite pad and washed with ethyl acetate. Thefiltrate was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as brown solid(0.118 g, 77% yield). MP: 171-173° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 8.21(s, 1H), 8.06(dd, J=7.9, 1.6Hz, 1H), 7.77(m, 1H), 7.50(dt, J=8.0,0.9Hz, 1H), 7.40-7.33(m, 6H), 5.43(s, 2H), 4.33(d, J=6.1z, 2H). Mass:423.88(M⁺).

EXAMPLE 602-((4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57a (0.500 g, 1.00 mmoles) in DMF (7 ml),ethanol (4 ml) and water (4 ml), N-Boc-Pyrazole-4-boronic acid pinacolester (0.445 g, 1.51 mmoles) and sodium carbonate (0.534 g, 5.04 mmoles)were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.229 g, 0.198 mmoles) was added undernitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as yellow solid (0.131 g, 29% yield). MP: 235-237° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 13.20(s,1H), 8.20(s,1H), 8.10(s,1H), 8.05(dd,J=8.0,1.7Hz, 1H), 7.78(s,1H), 7.76(m,1H), 7.49(dt, J=8.0,0.8Hz, 1H),7.39-7.31(m, 6H), 5.45(s,2H). Mass: 436.20(M⁺+1).

EXAMPLE 612-((4-amino-3-(3-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57a (0.250 g, 0.50 mmoles) in DMF (5 ml),ethanol (2.5 ml) and water (2.5 ml), 3-hydroxymethylphenylboronic acid(0.115 g, 0.757 mmoles) and sodium carbonate (0.267 g, 2.53 mmoles) wereadded and the system is degassed for 30 min Tetrakis triphenylphosphinePalladium (0.115 g, 0.099 mmoles) was added under nitrogen atmosphereand heated to 80° C. After 12 h, the reaction mixture was celitefiltered, concentrated and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as brown solid(0.116 g, 44% yield). MP: 219-223° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 8.23(s,1H), 8.05(dd, J=8.0, 1.6Hz, 1H), 7.77(m,1H), 7.58(s,1H),7.50(m, 3H), 7.44(d, J=8.5Hz, 1H), 7.41-7.31(m, 6H), 5.52(s,2H),5.27(t,J=5.8Hz, 1H), 4.57(d, J=5.7Hz, 2H). Mass: 476.31(M⁺+1).

EXAMPLE 622-((4-amino-3-(1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57a (0.500 g, 1.00 mmoles) in DMF (5 ml),ethanol (2.5 ml) and water (2.5 ml), 4-Indazoleboronic acid pinacolester (0.491 g, 2.00 mmoles) and sodium carbonate (0.533 g, 5.02 mmoles)were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.229 g, 0.197 mmoles) was added undernitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.040 g, 8% yield). MP: 248-252° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 13.24(s,1H), 8.27(s,1H), 8.07(dd, J=7.9,1.6Hz, 1H),8.01(s, 1H), 7.78(m,1H), 7.63(d, J=8.4Hz, 1H), 7.51-7.32(m,10H), 7.14(br s,1H),5.56(s, 1H). Mass: 486.04(M⁺+1).

EXAMPLE 632-((4-amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 78 (0.150 g, 0.654 mmoles) in DMF (5 ml),potassium carbonate (0.180 g, 1.30 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 5 (0.413 g, 1.30 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.130 g, 43% yield). MP: 244-247° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):δ 8.23(s, 1H), 8.05(dd, J=7.9, 1.6 Hz, 1H), 7.77(m, 1H), 7.58 (m, 1H),7.49-7.17(m, 10H), 5.52(s, 2H). Mass: 463.92(M⁺).

EXAMPLE 642-((4-amino-3-(3-hydroxypropyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of example 59 (0.170 g, 0.401 mmoles) in methanol (4 ml),palladium on charcoal 1 (10%, 0.050 g) was added and hydrogenated at 5kg/cm² for 48 h. The reaction mixture filtered through celite pad andwashed with methanol. The filtrate was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.072 g, 42% yield). MP: 182-184° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 8.11(s,1H), 8.05(dd, J=8.0, 1.6Hz, 1H),7.76(m,1H), 7.49(t, J=7.1Hz, 1H), 7.39-7.20(m, 8H), 4.62(t, J=4.6Hz,1H),3.45(q, J=6.1Hz, 2H), 2.92(t, J=7.4Hz, 2H), 1.78(m,2H). Mass:427.87(M⁺).

EXAMPLE 65N-(3-(4-amino-1-((4-oxo-3-phenyl-4H-chromen-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetamide

To a solution of Example 57a (0.250 g, 0.50 mmoles) in DMF (5 ml),ethanol (2.5 ml) and water (2.5 ml), 3-Acetamidophenyl boronic acid(0.116 g, 0.65 mmoles) and sodium carbonate (0.264 g, 2.50 mmoles) wereadded and the system is degassed for 30 min Tetrakis triphenylphosphinePalladium (0.109 g, 0.095 mmoles) was added under nitrogen atmosphereand heated to 80° C. After 12 h, the reaction mixture was celitefiltered, concentrated and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as yellow solid(0.080 g, 23% yield). MP: 122-123° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 10.13(s,1H), 8.06(dd, J=7.7, 1.4Hz, 1H),7.90(s, 1H),7.77(m,1H),7.57-7.47(m,3H), 7.48(m,3H), 7.37-7.29(m, 6H), 5.52(s,2H), 2.05(s, 3H).Mass: 503.05(M⁺+1).

EXAMPLE 662-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 79 (0.150 g, 0.58 mmoles) in DMF (5 ml),potassium carbonate (0.160 g, 1.16 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 5 (0.366 g, 1.16 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.120 g, 42% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.23(s,1H),8.05(dd, J=8.1,1.5Hz, 1H), 7.77(m, 1H), 7.49 (dt, J=8.1,0.9 Hz, 1H),7.44(d, J=8.4Hz, 1H), 7.38-7.30(m, 5H), 6.98(m,2H), 6.96(dt,J=7.9,2.3Hz, 1H), 5.51(s, 2H)., 3.81(s,3H).

EXAMPLE 66a2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 66 (0.100 g, 0.202 mmoles) in dichloromethane(15 ml), BBr₃ (1M in dichloromethane, 1.0 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as yellowsolid (0.035 g, 36% yield). MP: 260-262° C. ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 10.16(s,1H), 8.22(s, 1H), 8.06(dd, J=7.9, 1.5 Hz, 1H),7.78(m,1H), 7.50(dt, J=8.0,1.0 Hz, 1H), 7.44(d, J=8.5 Hz, 1H),7.37-7.31(m,5H), 6.86(t, J=1.5Hz, 1H), 6.82(dt, J=7.6, 2.3 Hz, 1H), 6.65(td, J=10.9,2.3 Hz, 1H), 5.50(s,2H). Mass: 480.02(M⁺+1).

EXAMPLE 672-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 79 (0.150 g, 0.58 mmoles) in DMF (5 ml),potassium carbonate (0.160 g, 1.16 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 77 (0.366 g, 1.16 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.120 g, 42% yield). MP: 115-117° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz):δ 8.21(s,1H), 8.06(dd, J=8.3,1.7 Hz, 1H), 7.80(m, 1H), 7.51 (m, 2H),7.39(q, J=8.0Hz, 1H), 7.18(m, 3H), 6.97(m,3H), 5.54(s, 2H),3.82(s, 3H).Mass: 511.80(M⁺).

EXAMPLE 682-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of example 67 (0.080 g, 0.156 mmoles) in dichloromethane(15 ml), BBr₃ (1M in dichloromethane, 0.8 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as off-whitesolid (0.035 g, 45% yield). MP: 235-237° C. ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 10.17(s,1H), 8.20(s, 1H), 8.06(dd, J=8.2,1.6 Hz, 1H),7.80(m,1H), 7.51(m,2H), 7.38(q, J=7.8 Hz, 1H), 7.17-7.07(m,3H), 6.84(t,J=1.7Hz, 1H), 6.81(td, J=79.3,2.1 Hz, 1H), 6.66(td, J=10.2,2.2 Hz, 1H),5.53(s,2H). Mass: 497.87(M⁺).

EXAMPLE 692-(1-(4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57b (0.400 g, 0.78 mmoles) in DMF (8 ml),ethanol (4 ml) and water (4 ml), N-Boc-pyrazole-4-boronic acid pinacolester (0.344 g, 1.17 mmoles) and sodium carbonate (0.413 g, 3.9 mmoles)were added and the system is degassed for 30 min Tetrakistriphenylphosphine. Palladium (0.171 g, 0.148 mmoles) was added undernitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.070 g, 19% yield). MP: 214-217° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 13.20(s,1H), 8.10(s,1H), 8.05(s,1H), 8.03(dd,J=8.0, 1.6Hz, 1H),7.82(m, 2H),7.61(d, J=8.0Hz, 1H), 7.51(dt, J=8.0,0.9Hz, 1H), (m,3H), 7.31-6.87(m, 5H), 5.92(q, J=7.1Hz, 1H), 1.87(d,J=7.1Hz, 3H). Mass: 449.852(M⁺).

EXAMPLE 702-(1-(4-amino-3-(1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57b (0.500 g, 0.98 mmoles) in DMF (10 ml),ethanol (4 ml) and water (4 ml), 6-Indazoleboronic acid pinacol ester(0.478 g, 1.96 mmoles) and sodium carbonate (0.519 g, 4.90 mmoles) wereadded and the system is degassed for 30 min Tetrakis triphenylphosphinePalladium (0.214 g, 0.185 mmoles) was added under nitrogen atmosphereand heated to 80° C. After 12 h, the reaction mixture was celitefiltered, concentrated and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol:dichloromethane to afford the title compound as brown solid(0.050 g, 10% yield). MP: 176-178° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 13.18(s,1H), 8.14(s,1H), 8.09(s,1H), 8.05(dd, J=8.0,1.6 Hz,1H),7.91(d,J=8.3Hz, 1H), 7.83(m,1H), 7.73(s, 1H), 7.63(d, J=8.3Hz, 1H), 7.52(dt,J=7.9,0.8 Hz, 1H), 7.41(dd, J=8.3,1.2Hz, 1H), 7.31-7.16(m, 5H), 6.01(q,J=6.9Hz, 1H), 1.92(d, J=7.1Hz, 3H). Mass: 500.04(M⁺+1).

EXAMPLE 712-(1-(4-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57b (0.500 g, 0.981 mmoles) in THF (14 ml),2-Methyl-3-butyn-2-ol (0.1 ml, 1.178 mmoles) diisopropylamine (0.70 ml,4.90 mmoles), copper(I) iodide (18.6 mg, 0.098 mmoles) and)Tetrakistriphenylphosphine Palladium (0.113 g, 0.098 mmoles) were addedand the system is degassed for 30 min. and heated to reflux for 4 h. Thereaction mixture filtered through celite pad and washed with ethylacetate. The filtrate was dried over sodium sulphate and concentratedunder reduced pressure. The crude product was purified by columnchromatography with methanol:dichloromethane to afford the titlecompound as brown solid (0.311 g, 68% yield). MP: 109-113° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 8.05(m,3H), 7.83(dt, J=8.6, 1.5Hz, 1H),7.61(d, J=8.4Hz, 1H), 7.52(t, J=7.2Hz, 1H), 7.30-7.11(m, 4H), 5.84(q,J=7.1z, 1H)5.74(s,1H), 1.82(d, J=7.0Hz, 3H),1.46(s,6H). Mass:466.09(M⁺+1).

EXAMPLE 722-(1-(4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (5.3 ml),ethanol (2.7 ml) and water (2.7 ml), N-Boc-pyrazole-4-boronic acidpinacol ester (0.334 g, 1.137 mmoles) and sodium carbonate (0.401 g,3.79 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.172 g, 0.149 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as off-white solid (0.040 g, 11% yield). MP: 223-226° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 13.2 (s,1H), 8.03(m,2H), 7.85(m,2H),7.68(d, J=8.3Hz, 1H), 7.52(t, J=7.7Hz, 1H), 7.25(m,1H), 7.07-6.93(m,3H), 5.92(q, J=6.9Hz, 1H), 1.87(d, J=7.0Hz, 3H). Mass: 467.84(M⁺).

EXAMPLE 73 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of intermediate 59 (2.0 g, 9.42 mmoles) in dichloromethane(20 ml), triethylamine (3.9 ml, 28.26 mmoles) was added followed byN-Boc-Alanine (1.90 g, 10.42 mmoles). To this mixture HATU (6.6 g, 17.37mmoles) was added and stirred at RT for 12 h. The reaction mixture wasquenched by the addition of water and extracted with dichloromethane.The organic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with ethyl acetate: petroleum ether to afford theisoflavone intermediate (1.70 g). To a solution of this intermediate(1.7 g) in dichloromethane (20 ml), trifluoroacetic acid (3 ml) wasadded and stirred at RT for 2 h. The reaction mixture was concentrated,basified with sodium bicarbonate solution, extracted with ethyl acetate.The organic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the amine intermediate (0.641 g). To asolution of this amine intermediate (0.30 g, 1.05 mmoles) intert-butanol (6 ml), N,N-diisopropylethylamine (0.36 ml, 2.17 mmoles)and 6-bromopurine (0.168 g, 0.847 mmoles) were added and refluxed for 24h. The reaction mixture was concentrated, diluted with water, extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as off-white solid (0.041 g, 10% yield). MP: 135-138° C. ¹H-NMR(δ ppm, DMSO-D₆, 400 MHz): δ 12.95(s,1H), 8.15(t, J=6.8Hz, 1H), 8.11(s,1H), 8.08(s, 1H), 8.03(d, J=7.8 Hz, 1H), 7.81(t, J=7.3Hz, 1H), 7.60 (d,J=8.3Hz, 1H), 7.49 (t, J=7.3Hz, 2H), 7.25(m,3H), 5.19(br m, 1H), 1.56(d,J=6.9Hz,3H). Mass: 384.12(M⁺+1).

EXAMPLE 74(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 73 (2.0 g, 8.05 mmoles) in dichloromethane(20 ml), triethylamine (3.3 ml, 24.17 mmoles) was added followed byN-Boc-L-Alanine (1.82 g, 9.66 mmoles). To this mixture HATU (6.12 g,16.11 mmoles) was added and stirred at RT for 12 h. The reaction mixturewas quenched by the addition of water and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with ethyl acetate: petroleum ether to afford theisoflavone intermediate (2.15 g). To a solution of this intermediate(2.1 g) in dichloromethane (20 ml), trifluoroacetic acid (4 ml) wasadded and stirred at RT for 2 h. The reaction mixture was concentrated,basified with sodium bicarbonate solution, extracted with ethyl acetate.The organic layer was dried over sodium sulphate and concentrated underreduced pressure to afford the amine intermediate (0.700 g). To asolution of this amine intermediate (0.450 g, 1.49 mmoles) intert-butanol (7 ml), N,N-diisopropylethylamine (0.52 ml, 2.98 mmoles)and 6-chloropurine (0.184 g, 1.194 mmoles) were added and refluxed for24 h. The reaction mixture was concentrated, diluted with water,extracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol: ethyl acetate to affordthe title compound as off-white solid (0.060 g, 12% yield). MP: 203-206°C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 12.96(s,1H), 8.15(m, 2H), 8.08(s,1H), 7.70(m, 3H), 7.49(q, J=7.3Hz, 1H), 7.24 (m, 3H), 5.18(br m, 1H),1.55(d, J=7.1Hz,3H). Mass: 420.17(M⁺+1).

EXAMPLE 752-((4-amino-3-(1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57a (0.700 g, 1.40 mmoles) in DMF (7 ml),ethanol (3.2 ml) and water (3.2 ml), 6-Indazoleboronic acid pinacolester (0.687 g, 2.81 mmoles) and sodium carbonate (0.745 g, 7.03 mmoles)were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.320 g, 0.277 mmoles) was added undernitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.020 g, 3% yield). MP: 140-143° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 13.18(s,1H), 8.24(s,1H), 8.13(s,1H), 8.06(dd,J=7.9, 1.6Hz, 1H), 7.78(m,2H), 7.49-7.30(m, 7H), 6.89(q,J=7.7Hz,1H),5.53(s, 2H). Mass: 485.76(M⁺+1).

EXAMPLE 762-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 79 (0.160 g, 0.617 mmoles) in DMF (6 ml),potassium carbonate (0.171 g, 1.16 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.429 g, 1.23 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.160 g, 49% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.08(s,1H),8.04(dd, J=8.0,1.6Hz, 1H), 7.85(m, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.53(dt,J=7.9,0.9Hz, 1H), 7.31(br s, 1H), 7.07(dt, J=8.6,2.1Hz, 1H), 6.97(m,5H),6.03(q, J=7.1Hz, 1H),3.82(s,3H), 1.90(d, J=7.0Hz, 3H).

EXAMPLE 76a2-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 76 (0.160 g, 0.304 mmoles) in dichloromethane(25 ml), BBr₃ (1M in dichloromethane, 1.6 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as off-whitesolid (0.080 g, 51% yield). MP: 271-273° C. ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 10.17(s,1H), 8.06(s, 1H), 8.05(dd, J=7.9,1.4Hz, 1H), 7.86(dt,J=8.5,1.5Hz, 1H), 7.68(d, J=8.3Hz, 1H),7.53(t, J=7.9Hz, 1H), 7.28(br s,1H), 7.05(dt, J=6.8,2.0 Hz, 1H), 6.91(br s, 2H), 6.86(s,1H), 6.79(d,J=9.4Hz, 1H), 6.66(td, J=10.3,2.1 Hz, 1H),6.05(q, J=6.7Hz, 1H),1.88(d,J=7.1Hz, 3H). Mass: 511.80(M⁺).

EXAMPLE 772-(1-(4-amino-3-(1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.350 g, 1.00 mmoles) in DMF (8 ml),ethanol (4 ml) and water (4 ml), 4-Indazoleboronic acid pinacol ester(0.322 g, 1.32 mmoles) and sodium carbonate (0.349 g, 3.3 mmoles) wereadded and the system is degassed for 30 min Tetrakis triphenylphosphinePalladium (0.150 g, 0.130 mmoles) was added under nitrogen atmosphereand heated to 80° C. After 12 h, the reaction mixture was celitefiltered, concentrated and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol:dichloromethane to afford the title compound as off-white solid(0.045 g, 13% yield). MP: 231-233° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 13.25(s,1H), 8.10(s,1H), 8.06(m, 2H), 7.86(m,1H), 7.66(t, J=9.0Hz,2H), 7.54(m, 2H), 7.33(t, J=6.7Hz, 2H), 7.11-7.06(m,3H), 6.07(q,J=7.1Hz, 1H),1.94(d, J=7.0Hz, 3H). Mass: 517.96(M⁺).

EXAMPLE 782-(1-(4-amino-3-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.350 g, 0.661 mmoles) in DMF (6 ml),ethanol (3 ml) and water (3 ml), 3,5-Dimethylpyrazole-4-boronic acidpinacol ester (0.191 g, 0.859 mmoles) and sodium carbonate (0.350 g,3.30 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.150 g, 0.130 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as brown solid (0.025 g, 7% yield). MP: 240-243° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 12.44(s,1H), 8.04(dd, J=8.0,1.6Hz, 1H),8.01(s,1H), 7.85(s,1H), 7.61(d, J=8.3Hz, 1H), 7.52(dt, J=7.9,0.7 Hz,1H), 7.33(br m,1H), 7.12-6.95(m, 3H), 5.97(q, J=7.0Hz, 1H), 2.09(s,6H),1.86(d, J=7.0Hz, 3H). Mass: 495.84(M⁺).

EXAMPLE 792-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), 3-Methylindazole-6-boronic acid pinacolester 97 (0.391 g, 1.517 mmoles) and sodium carbonate (0.401 g, 3.79mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.172 g, 0.149 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol:dichloromethane to afford the titlecompound as yellow solid (0.095 g, 23% yield). MP: 214-217° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 12.75(s,1H), 8.08(s,1H), 8.05(dd, J=7.9,1.4Hz,1H), 7.86(m,2H), 7.68(d, J=8.3Hz, 1H), 7.62(s,1H), 7.53(t, J=7.3Hz, 1H),7.33(d, J=8.5Hz, 1H), 7.31(br s, 1H), 7.07(dt, J=8.9,2.1Hz, 1H), 6.93(m,2H), 6.07(q, J=6.7Hz, 1H), 2.51(s,3H), 1.91(d, J=7.0Hz, 3H). Mass:532.03(M⁺+1).

EXAMPLE 802-(1-(4-amino-3-(1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.500 g, 0.758 mmoles) in DMF (4.5 ml),ethanol (2.3 ml) and water (2.3 ml), Indazole-6-boronic acid pinacolester (0.462 g, 1.89 mmoles) and sodium carbonate (0.502 g, 4.74 mmoles)were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.215 g, 0.186 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.080 g, 16% yield). MP: 206-208° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 13.19(s,1H), 8.14(s,1H), 8.08(s,1H),8.05(dd,J=7.9,1.5Hz, 1H), 7.90(d, J=8.3Hz, 1H), 7.86(m,1H), 7.71(s,1H), 7.69(d,J=8.4Hz, 1H), 7.53(t, J=7.1Hz, 1H), 7.39(dd, J=8.2,1.1Hz, 1H),7.30(m,2H), 7.07(dt, J=8.7,2.6Hz, 1H), 6.92(br m, 2H), 6.06(q, J=7.1Hz,1H), 1.91(d, J=7.0Hz, 3H). Mass: 517.96(M⁺).

EXAMPLE 812-(1-(4-amino-3-(2-(hydroxymethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.300 g, 0.568 mmoles) in DMF (3 ml),ethanol (1.5 ml) and water (1.5 ml), 2-Hydroxymethylphenylboronic acid(0.173 g, 1.137 mmoles) and sodium carbonate (0.301 g, 2.844 mmoles)were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.129 g, 0.112 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as off-white solid (0.090 g, 31% yield). MP: 185-189° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 8.09(s,1H), 8.04(dd, J=7.9,1.4Hz, 1H),7.84(m,1H), 7.66-7.35(m,10H), 7.17(dt, J=10.8,1.4Hz, 1H), 7.04(m,1H),6.01(q, J=6.7Hz, 1H), 5.13(t, J=5.7Hz, 1H), 4.54(m,2H), 1.87(d, J=7.1Hz,3H). Mass: 508.16(M⁺+1).

EXAMPLE 822-(1-(4-amino-3-(4-fluoro-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 80 (0.120 g, 0.617 mmoles) in DMF (6 ml),potassium carbonate (0.128 g, 0.925 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.323 g, 1.23 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.075 g, 31% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.07(s,1H),8.04(d, J=7.0Hz, 1H), 7.85 (t, J=7.1Hz, 1H), 7.68(d, J=8.5Hz, 1H),7.61(m,1H), 7.53(t, J=7.1Hz, 1H), 7.36(m,2H), 7.16(m,1H), 7.07(t,J=6.7Hz, 1H), 6.93(br s,2H), 6.03(q, J=7.0Hz, 1H),3.88(s,3H), 1.90(d,J=7.0Hz, 3H).

EXAMPLE 82a2-(1-(4-amino-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 82 (0.075 g, 0.142 mmoles) in dichloromethane(15 ml), BBr₃ (1M in dichloromethane, 1 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N Hal solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as palegreen solid (0.040 g, 55% yield). MP: 241-244° C. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 10.15(s,1H), 8.05(s, 1H), 8.05(dd, J=8.6,1.5Hz,1H), 7.86(m, 1H), 7.68(d, J=8.4Hz, 1H),7.53(t, J=7.4Hz, 1H), 7.28(m,2H),7.20(dd, J=8.5,1.9 Hz, 1H), 7.05(m,4H),6.04(q, J=7.1Hz, 1H),1.88(d,J=7.1Hz, 3H). Mass: 511.94(M⁺).

EXAMPLE 832-(1-(4-amino-3-(3-hydroxyprop-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example -57c (0.400 g, 0.755 mmoles) in THF (10 ml),propargyl alcohol (0.051 g, 0.906 mmoles) diisopropylamine (0.53 ml,3.77 mmoles), copper (I) iodide (14 mg, 0.075 mmoles) and) Tetrakistriphenylphosphine Palladium (0.087 g, 0.075 mmoles) were added and thesystem is degassed for 30 min and heated to reflux for 4 h. The reactionmixture filtered through celite pad and washed with ethyl acetate. Thefiltrate was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as brown solid(0.106 g, 23% yield). MP: 171-173° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ11.36(s,1H), 8.19(dd, J=7.9, 1.2Hz, 1H), 7.70(dt, J=8.6,1.5Hz, 1H),7.47(d, J=8.4Hz, 1H), 7.42(t, J=7.5Hz, 1H), 7.38(m, 2H), 7.07(t,J=8.2Hz, 1H), 6.99(m,2H),6.00(q, J=7.0Hz, 1H), 4.55(s, 2H), 1.97(d,J=7.1Hz, 1H). Mass: 456.08(M⁺+1).

EXAMPLE 842-(1-(4-amino-3-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 81 (0.130 g, 0.50 mmoles) in DMF (4 ml),potassium carbonate (0.139 g, 1.00 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.350 g, 1.00 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.163 g,60% yield). MP: 222-224° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.06(s,1H), 8.04(dd, J=7.9,1.5 Hz, 1H), 7.85(m, 1H), 7.68(dd, J=8.4 Hz,1H), 7.52(t, J=7.4Hz, 1H), 7.37-7.28(m, 4H), 7.07(dt, J=8.9,2.4Hz, 1H),6.93(br s,2H), 6.05(q, J=7.1 Hz, 1H), 3.89(s,3H), 1.89(d, J=7.0Hz, 3H).Mass: 525.94(M⁺).

EXAMPLE 852-(1-(4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of example 84 (0.100 g, 0.190 mmoles) in dichloromethane(4 ml), BBr₃ (1M in dichloromethane, 1 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as palegreen solid (0.061 g, 63% yield). MP: 244-247° C. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 10.19(s,1H), 8.04(s, 1H), 8.04(dd, J=8.0,1.4 Hz,1H), 7.85(m,1H), 7.68(d, J=8.4Hz, 1H), 7.52(t, J=7.2Hz, 1H), 7.33(m,2H),7.24(dd, J=8.2,1.4 Hz, 1H), 7.09-6.91(m,4H), 6.00(q, J=7.0 Hz,1H),1.88(d, J=7.0 Hz, 1H). Mass: 511.94(M⁺).

EXAMPLE 862-(1-(4-amino-3-(3-chloro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 82 (0.100 g, 0.362 mmoles) in DMF (4 ml),potassium carbonate (0.100 g, 0.725 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.252 g, 0.725 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.132 g, 67% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.08(s,1H),8.04(d, J=6.8Hz, 1H), 7.85 (m, 1H), 7.67(d, J=8.4Hz, 1H), 7.52(t,J=7.5Hz, 1H), 7.28(br s, 1H), 7.17(s,1H), 7.12(s,1H), 7.05-6.94(m,4H),6.03(q, J=7.0Hz, 1H),3.82(s,3H), 1.90(d, J=7.0Hz, 3H).

EXAMPLE 86a2-(1-(4-amino-3-(3-chloro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 86 (0.100 g, 0.184 mmoles) in dichloromethane(4 ml), BBr₃ (1M in dichloromethane, 1 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as palegreen solid (0.032 g, 33% yield). MP: 122-124° C. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 10.19(s,1H), 8.06(s, 1H), 8.04(dd, J=7.9,1.5 Hz,1H), 7.86(m,1H), 7.67(d, J=8.3Hz, 1H), 7.53(t, J=7.1Hz, 1H), 7.28(brs,1H), 7.06-6.87(m,6H), 6.03(q, J=6.9 Hz, 1H),1.88(d, J=7.1Hz, 1H).Mass: 528.11(M⁺+1).

EXAMPLE 872-(1-(4-amino-3-(3-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 83 (0.200 g, 0.677 mmoles) in DMF (8 ml),potassium carbonate (0.187 g, 1.354 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.472 g, 1.354 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as Off-white solid (0.058g, 15% yield). MP: 155-157° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.09(s,1H), 8.04(dd, J=6.7,1.3 Hz, 1H), 7.86 (m, 1H), 7.68-7.45 (m, 8H),7.28(br s, 1H), 7.03-6.91(m, 3H), 6.06(q, J=7.2 Hz, 1H), 1.90(d,J=7.1Hz, 3H). Mass: 562.13(M⁺+1).

EXAMPLE 882-(1-(4-amino-3-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 84 (0.200 g, 0.829 mmoles) in DMF (4 ml),potassium carbonate (0.229 g, 1.658 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.576 g, 1.658 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.180 g, 43% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.05(m, 2H),7.85(m,1H), 7.68(dd, J=8.4,5.7Hz, 1H), 7.54(m,3H), 7.28(br s, 1H),7.09-6.90(m,5H), 6.01(q, J=7.0Hz, 1H),3.82(s,3H), 1.89(d, J=7.1Hz, 3H).

EXAMPLE 88a2-(1-(4-amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 88 (0.150 g, 0.295 mmoles) in dichloromethane(4 ml), BBr₃ (1M in dichloromethane, 1.5 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as off-whitesolid (0.048 g, 33% yield). MP: 244-247° C. ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 9.79(s,1H), 8.04(s, 1H), 8.04(dd, J=8.5,1.4 Hz, 1H), 7.85(m,1H),7.68(d, J=8.5Hz, 1H), 7.53(t, J=7.6Hz, 1H), 7.42(d, J=8.5Hz, 2H),7.28(br s,1H), 7.06(t, J=8.5 Hz, 1H), 6.91(d, J=8.5Hz, 2H), 6.91(brs,2H), 6.00(q, J=7.1 Hz, 1H),1.88(d, J=7.0 Hz, 3H). Mass: 492.69(M⁺−1).

EXAMPLE 892-((6-amino-9H-purin-9-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Adenine (0.243 g, 1.80 mmoles) in DMF (5 ml), potassiumcarbonate (0.248 g, 1.80 mmoles) was added and stirred at RT for 10 min.To this mixture intermediate 77 (0.300 g, 0.900 mmoles) was added andstirred for 12 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by column chromatography with methanol: dichloromethane toafford the title compound as yellow solid (0.080 g, 23% yield). MP:224-227° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.12(s, 1H), 8.07(s,1H), 8.05(dd, J=7.7, 1.2Hz, 1H), 7.79(m, 1H), 7.55(m, 3H), 7.28-7.21(m,5H), 5.36(s, 2H).Mass: 388.04(M⁺+1).

EXAMPLE 902-(1-(4-amino-3-(4-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 85 (0.120 g, 0.462 mmoles) in DMF (6 ml),potassium carbonate (0.127 g, 0.924 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.321 g, 0.924 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.080 g, 33% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.04(d,J=6.6Hz,1H), 8.00(s,1H), 7.85(t, J=8.7Hz, 1H), 7.66-7.49(m,4H), 7.38(t,J=7.3Hz, 1H), 7.29(br s, 1H), 7.08-6.85(m,5H), 5.99(q, J=7.0Hz,1H),3.77(s,3H), 1.87(d, J=7.1Hz, 3H).

EXAMPLE 90a2-(1-(4-amino-3-(4-fluoro-2-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 90 (0.080 g, 0.152 mmoles) in dichloromethane(4 ml), BBr₃ (1M in dichloromethane, 0.8 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as off-whitesolid (0.027 g, 35% yield). MP: 235-237° C. ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 10.66(s,1H), 8.04(d, J=9.8 Hz, 1H), 8.02(s,1H),7.84(t,J=7.0Hz,1H), 7.66(d, J=8.3Hz, 1H), 7.52(t, J=7.9Hz, 1H), 7.35(t,J=7.2Hz, 2H), 7.10(t, J=8.4 Hz, 1H), 6.96(br s,2H), 6.79(m, 2H), 5.98(q,J=7.0 Hz, 1H),1.88(d, J=7.1Hz, 3H). Mass: 512.22(M⁺+1).

EXAMPLE 912-((4-amino-3-(3-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57a (0.400 g, 0.804 mmoles) in DMF (10 ml),ethanol (5 ml) and water (5 ml), 3-Acetamidophenyl boronic acid (0.187g, 1.045 mmoles) and sodium carbonate (0.426 g, 4.02 mmoles) were addedand the system is degassed for 30 min Palladium tetrakistriphenylphosphine (0.183 g, 0.158 mmoles) was added under nitrogenatmosphere and heated to 80° C. After 12 h, the reaction mixture wascelite filtered, concentrated and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. To the concentrate ethanol (5 ml) and Con.HCl (0.5 ml)were added and refluxed for 2 h. The reaction mixture was basified withsodium carbonate solution and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as yellow solid(0.140 g, 38% yield). MP: 157-159° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 8.21(s,1H), 8.06(dd, J=7.8,1.3Hz, 1H),7.77(dt, J=8.6,1.5Hz,1H),7.49(t, J=7.4Hz, 1H),, 7.37-7.29(m,5H), 7.17(t, J=7.7Hz, 1H),6.84(s,1H), 6.71(d, J=7.5Hz, 1H),6.65(d, J=7.9Hz, 1H), 5.51(s,2H),5.34(s, 2H). Mass: 460.84(M⁺).

EXAMPLE 922-((4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57a (0.462 g, 0.930 mmoles) in DMF (6 ml),ethanol (3 ml) and water (3 ml), N-Boc-3-methylindazole-6-boronic acidpinacol ester 98 (0.500 g, 1.39 mmoles) and sodium carbonate (0.295 g,2.79 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.057 g, 0.046 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as off-white solid (0.120 g, 26% yield). MP: 2924-295° C.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 12.74(s,1H), 8.24(s,2H), 8.06(dd,J=7.9,1.5Hz, 1H), 7.84(d, J=8.3Hz, 1H), 7.75(m,1H), 7.63(s,1H), 7.49(t,J=7.3Hz, 1H), 7.45(d, J=8.3Hz, 1H), 7.38-7.32(m, 6H), 5.53(s, 2H),2.51(s, 3H). Mass: 499.90(M⁺).

EXAMPLE 932-(1-(4-amino-3-(2-aminopyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), 2-aminopyrimidine-5-boronic acid (0.184g, 1.327 mmoles) and sodium carbonate (0.351 g, 3.318 mmoles) were addedand the system is degassed for 30 min TetrakistriphenylphosphinePalladium (0.151 g, 0.130 mmoles) was added under nitrogen atmosphereand heated to 80° C. After 12 h, the reaction mixture was celitefiltered, concentrated and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as brown solid(0.045 g, 14% yield). MP: 264-268° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 8.38(s,2H), 8.05(s,1H), 8.03(d, J=7.9,Hz, 1H), 7.85(m,1H), 7.68(d,J=8.3Hz, 1H), 7.52(t, J=7.3Hz, 1H), 7.29(br s, 1H), 7.07-6.93(m, 5H),5.99(q, J=7.0Hz, 1H),1.88 (d, J=7.0Hz, 3H). Mass: 494.86(M⁺).

EXAMPLE 942-(1-(4-amino-3-(1H-indol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), 6-indoleboronic acid pinacol ester(0.213 g, 1.327 mmoles) and sodium carbonate (0.351 g, 3.318 mmoles)were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.151 g, 0.130 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.050 g, 15% yield). MP: 222-225° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 11.27(s,1H), 8.06(s,1H), 8.05(dd, J=8.0,1.6Hz,1H), 7.86(m,1H), 7.69(d, J=7.2Hz, 2H), 7.62(s,1H), 7.53(t, J=8.1Hz, 1H),7.45(t, J=2.8Hz, 1H), 7.28(m, 2H), 7.06-6.89(m, 3H), 6.50(s,1H), 6.04(q,J=7.1Hz, 1H),1.91(d, J=7.1Hz, 3H). Mass: 516.84(M⁺).

EXAMPLE 952-(1-(4-amino-3-(4-chloro-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 86 (0.90 g, 0.3262 mmoles) in DMF (3 ml),potassium carbonate (0.090 g, 0.653 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.227 g, 0.653 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as green solid (0.055 g,31% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.08(s,1H), 8.04 (dd,J=8.0,1.6Hz, 1H), 7.85(m,1H), 7.68(d, J=8.4Hz, 1H), 7.55(m,2H), 7.29(brs, 1H), 7.25(d, J=1.7Hz, 1H), 7.19(dd, J=8.1,1.8Hz, 1H), 7.08(dt,J=8.8,2.4Hz, 1H),6.92 (br s,2H), 6.02(q, J=7.0Hz, 1H),3.90(s,3H),1.90(d, J=7.1Hz, 3H).

EXAMPLE 95a2-(1-(4-amino-3-(4-chloro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 95 (0.055 g, 0.1012 mmoles) in dichloromethane(4 ml), BBr₃ (1M in dichloromethane, 0.5 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as palegreen solid (0.025 g, 86% yield). MP: 134-136° C. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 10.50(s,1H),8.18(s,1H), 8.05(d, J=8.0Hz, 1H),7.87(t, J=7.0Hz,1H), 7.64(d, J=8.4Hz, 1H), 7.54(t, J=7.6Hz, 1H), 7.50(d,J=8.0Hz, 2H), 7.29(br s,1H), 7.21(d, J=1.6Hz, 1H), 7.07-6.93(m, 4H),6.07(q, J=6.9 Hz, 1H),1.90(d, J=7.0Hz, 3H). Mass: 527.76(M⁺).

EXAMPLE 962-(1-(4-amino-3-(2-chloro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 87 (0.060 g, 0.217 mmoles) in DMF (2 ml),potassium carbonate (0.060 g, 0.435 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.151 g, 0.435 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as green solid (0.030 g,30% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.05(s,1H), 8.04 (dd,J=7.9,1.3Hz, 1H), 7.85(m,1H), 7.63(d, J=8.1Hz, 2H), 7.55(m,2H), 7.32(brs, 1H), 7.18(m, 2H), 7.00(d, J=3.0Hz, 1H), 6.99(br s,1H), 6.02(q,J=7.0Hz, 1H),3.90(s,3H), 1.90(d, J=7.1Hz, 3H).

EXAMPLE 96a2-(1-(4-amino-3-(2-chloro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 96 (0.030 g, 0.055 mmoles) in dichloromethane(3 ml), BBr₃ (1M in dichloromethane, 0.27 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated to afford the title compound as pale green solid (0.018 g,62% yield). MP: 192-195° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ9.95(s,1H),8.15(s,1H), 8.05(dd, J=7.9,1.2Hz, 1H), 7.86(m, 1H),7.65-7.49(m,4H), 7.39(d, J=8.7Hz, 1H), 7.35(br s,1H), 7.11(t, J=7.5Hz,1H), 6.97(dd, J=7.6,3.2Hz, 1H), 6.86(d, J=2.8Hz, 1H), 6.07(q, J=6.9 Hz,1H),1.88(d, J=7.0Hz, 3H). Mass: 527.90(M).

EXAMPLE 972-(1-(4-amino-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 88 (0.220 g, 0.808 mmoles) in DMF (8 ml),potassium carbonate (0.223 g, 1.61 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 36 (0.562 g, 1.61 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.163 g,60% yield). MP: 232-235° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.05(s,1H), 8.04(dd, J=8.0,1.5 Hz, 1H), 7.85(m, 1H), 7.68(dd, J=8.4 Hz,1H), 7.52(t, J=7.2Hz, 1H), 7.29(br s, 1H), 7.13-6.93(m, 6H), 6.01(q,J=7.1 Hz, 1H), 3.80(s,6H), 1.90(d, J=7.1Hz, 3H). Mass: 538.05(M⁺+1).

EXAMPLE 982-(1-(4-amino-3-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of example 97 (0.180 g, 0.0.335 mmoles) in dichloromethane(10 ml), BBr₃ (1M in dichloromethane, 1.8 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated to afford the title compound as off-white pale solid (0.040g, 24% yield). MP: 193-195° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ9.27(s,1H), 9.22(s,1H), 8.05(dd, J=7.3,1.4Hz, 1H), 8.03(s,1H), 7.86(m,1H), 7.68(d, J=8.4Hz, 1H), 7.53(t, J=7.7Hz, 1H), 7.35(s,1H), 7.27(br s,1H), 7.05-6.86(m,5H), 6.02(q, J=7.0 Hz, 1H),1.87(d, J=7.0Hz, 3H). Mass:509.84(M).

EXAMPLE 992-((4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.477 g, 0.930 mmoles) in DMF (5.3 ml),ethanol (2.6 ml) and water (2.6 ml), N-Boc-3-methyl-6-indazoleboronicacid pinacol ester 98 (0.500 g, 1.395 mmoles) and sodium carbonate(0.295 g, 3.318 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.053 g, 0.046 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as off-white solid (0.100 g, 20% yield). MP: 246-248° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 12.75(s,1H), 8.22(s,1H), 8.06(dd,J=8.5,1.8Hz, 1H), 7.84(d, J=8.3Hz, 1H), 7.80(m,1H), 7.62(s,1H), 7.51(d,J=8.2Hz, 2H), 7.39-7.31(m, 2H), 7.18(m, 2H), 7.12(dt, J=8.3,2.6Hz, 1H),5.56(s,2H), 2.51(s,3H). Mass: 517.51(M⁺).

EXAMPLE 1002-(1-(4-amino-3-(1H-indol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), 5-indoleboronic acid pinacol ester(0.213 g, 1.327 mmoles) and sodium carbonate (0.351 g, 3.318 mmoles)were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.151 g, 0.130 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.044 g, 13% yield). MP: 197-199° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 11.30(s,1H), 8.06(s,1H), 8.05(dd, J=7.9,1.2Hz,1H), 7.85(m,1H), 7.77(s,1H), 7.69(d, J=8.4Hz, 1H), 7.55(m, 2H), 7.44(t,J=2.8Hz, 1H), 7.35(m, 2H), 7.09-6.94(m, 3H), 6.54(m,1H), 6.05(q,J=7.0Hz, 1H),1.91(d, J=7.0Hz, 3H). Mass: 516.91(M⁺).

EXAMPLE 1012-(1-(4-Amino-3-(3-methyl-1H-indol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.400 g, 0.757 mmoles) in DMF (5 ml),ethanol (2.5 ml) and water (2.5 ml), 3-methyl-5-indoleboronic acidpinacol ester (0.292 g, 1.136 mmoles) and sodium carbonate (0.240 g,2.272 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.040 g, 13% yield). MP: 171-173° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 10.96(s,1H), 8.06(s,1H), 8.04(dd, J=7.9,1.4Hz,1H), 7.85(m,1H), 7.68(d, J=8.1Hz, 2H), 7.52(d, J=7.2Hz, 1H), 7.49(d,J=8.3Hz, 1H), 7.32(dd, J=8.2,1.4Hz, 2H), 7.20(s, 1H), 7.08(dt,J=11.2,2.7Hz, 1H), 6.93(br s,2H), 6.04(q, J=7.0Hz, 1H),2.28(s,3H),1.92(d, J=7.0Hz, 3H). Mass: 530.98(M⁺).

EXAMPLE 102 tert-butyl(5-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophen-2-yl)methylcarbamate

To a solution of Example 57c (0.300 g, 0.566 mmoles) in dioxane (4 ml),2-N-Boc-aminomethylthiophene-5-boronic acid (0.186 g, 0.725 mmoles) andpotassium acetate (0.168 g, 1.887 mmoles) were added and the system isdegassed for 30 min. Tetrakistriphenylphosphine Palladium (0.052 g,0.045 mmoles) was added under nitrogen atmosphere and heated to 80° C.After 12 h, the reaction mixture filtered through celite and extractedwith ethyl acetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.070 g, 20% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 8.06(s,1H), 8.05(dd, J=8.0,1.6Hz, 1H), 7.85(m,1H), 7.65(d,J=8.5Hz, 1H), 7.55(m, 3H), 7.32-7.22(m, 3H), 7.12(m, 2H), 6.98(d,J=3.5Hz, 1H), 6.92(br s,1H), 5.99(q, J=7.1Hz, 1H),4.29(d, J=6.1Hz, 2H),1.87(d, J=7.0Hz, 3H).

Example 102a2-(1-(4-amino-3-(5-(aminomethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 102 (0.070 g, 0.114 mmoles) in dichloromethane(3 ml), TFA (0.1 ml) was added under nitrogen atmosphere stirred at roomtemperature. After 3 h, the reaction mixture was concentrated,neutralised with sodium bicarbonate solution and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as yellow solid (0.030 g, 51% yield). MP: 275-278° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 8.06(s,1H), 8.05(dd, J=7.9,1.5 Hz, 1H),7.85(m,1H), 7.66(d, J=8.3 Hz, 1H), 7.53(t, J=7.2 Hz, 1H), 7.28(m, 2H),7.09(d, J=3.5 Hz, 1H), 7.05(dt, J=8.7,2.4 Hz, 1H), 6.92(br s,2H),6.02(q, J=7.1 Hz, 1H),4.03(s,2H), 1.87(d, J=7.1 Hz, 3H). Mass:513.27(M⁺+1⁾.

Example 1032-((4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of Example 57d (0.300 g, 0.584 mmoles) in DMF (3 ml),ethanol (1.5 ml) and water (1.5 ml), N-Boc-3-methyl-6-indazoleboronicacid pinacol ester 98 (0.314 g, 0.877 mmoles) and sodium carbonate(0.185 g, 1.754 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.033 g, 0.029 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.012 g, 4% yield). MP: 277-279° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 12.75(s,1H), 8.23(s,1H), 7.84(d, J=8.2 Hz,1H), 7.74(dd, J=8.2,3.0 Hz, 1H), 7.66(m,2H), 7.59(dd, J=9.2,4.2 Hz, 1H),7.38-7.32(m, 6H), 6.54(s,2H), 2.51(s,3H). Mass: 518.17(M⁺+1⁾.

Example 1042-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenyl-4H-chromen-4-one

To a solution of Example 57b (0.350 g, 0.684 mmoles) in DMF (3.5 ml),ethanol (1.7 ml) and water (1.7 ml), 3-methyl-6-indazoleboronic acidpinacol ester 97 (0.353 g, 1.369 mmoles) and sodium carbonate (0.217 g,2.05 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.040 g, 0.034 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.073 g, 21% yield). MP: 249-252° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 12.75(s,1H), 8.09(s,1H), 8.05(dd, J=8.0,1.6Hz, 1H), 7.85(d, J=8.2 Hz, 1H), 7.81(m,1H), 7.64(s,1H), 7.62(d, J=8.4Hz, 1H), 7.51(t, J=7.3 Hz, 1H), 7.36(dd, J=9.3,1.0 Hz, 1H), 7.29(m,3H),7.15(br s,2H), 6.01(q, J=7.0 Hz, 1H), 2.52(s,3H), 1.92(d, J=7.0 Hz, 3H).Mass: 514.18(M⁺+1⁾.

Example 1052-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of Example 57e (0.400 g, 0.758 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), 3-methyl-6-indazoleboronic acid pinacolester 97 (0.391 g, 1.517 mmoles) and sodium carbonate (0.241 g, 2.27mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.044 g, 0.037 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as yellow solid (0.065 g, 15% yield). MP: 253-255° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 12.75(s,1H), 8.08(s,1H), 7.85(d, J=8.3 Hz,1H), 7.75(m,3H), 7.63(s,1H), 7.35(dd, J=8.4,1.2 Hz, 1H), 7.28(m,3H),7.14(br s,2H), 6.00(q, J=7.1 Hz, 1H), 2.52(s,3H), 1.91(d, J=7.1 Hz, 3H).Mass: 532.03(M⁺+1⁾.

Example 1062-(1-(4-amino-3-(3-methyl-1H-indazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), N-Boc-3-methyl, 5-indazoleboronic acidpinacol ester (0.356 g, 0.994 mmoles) and sodium carbonate (0.210 g,0.98 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.038 g, 0.033 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as pale brown solid (0.050 g, 14% yield). MP: 254-256° C.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 12.79(s,1H), 8.07(s,1H), 8.04(dd,J=8.0,1.6 Hz, 1H), 7.87(s,1H), 7.85(m,1H), 7.69(d, J=8.3 Hz, 1H),7.60-7.49(m,3H), 7.29(br s,1H), 7.07(dt, J=8.6,2.3 Hz, 1H), 6.93(brs,2H), 6.05(q, J=7.1 Hz, 1H), 2.51(s,3H), 1.91(d, J=7.0 Hz, 3H). Mass:532.03(M⁺+1⁾.

Example 107N-(4-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetamide

To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (3.5 ml),ethanol (1.75 ml) and water (1.75 ml), 4-Acetamidophenyl boronic acid(0.237 g, 1.32 mmoles) and sodium carbonate (0.211 g, 1.99 mmoles) wereadded and the system is degassed for 30 min Palladium tetrakistriphenylphosphine (0.038 g, 0.033 mmoles) was added under nitrogenatmosphere and heated to 80° C. After 12 h, the reaction mixture wascelite filtered, concentrated and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as yellow solid (0.080 g, 24% yield). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 10.12(s,1H), 8.06(s,1H), 8.04(dd, J=8.0,1.4 Hz, 1H),7.85(m,1H), 7.74(d, J=8.5 Hz, 2H), 7.68(d, J=8.2 Hz, 1H), 7.58(m,3H),7.32(m,1H), 7.06(dt, J=8.2,2.4 Hz, 1H), 6.82(m,2H), 6.02(q, J=7.0 Hz,1H), 2.06(s,3H), 1.89(d, J=7.1 Hz, 3H).

Example 107a2-(1-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 107 (0.080 g, 0.149 mmoles) in ethanol (5 ml),Con.HCl (0.5 ml) was added and refluxed for 2 h. The reaction mixturewas basified with sodium carbonate solution and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.020 g, 27% yield). MP: 91-94° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 8.04(dd, J=8.3,1.5 Hz, 1H), 8.02(s,1H),7.85(m,1H), 7.67(d, J=8.4 Hz, 1H), 7.53(t, J=7.6 Hz, 2H),7.29(m,3H),7.06(dt, J=8.7,2.3 Hz, 1H), 6.91(br s,1H), 6.68(d, J=8.4 Hz, 2H),6.00(q, J=7.0 Hz, 1H), 5.42(s,2H), 1.87(d, J=7.0 Hz, 3H). Mass:492.83(M⁺).

Example 1082-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57f (0.400 g, 0.733 mmoles) in DMF (5 ml),ethanol (2.5 ml) and water (2.5 ml), N-Boc-3-methyl-6-indazoleboronicacid pinacol ester 98 (0.393 g, 1.099 mmoles) and sodium carbonate(0.233 g, 2.19 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as brown solid (0.045 g, 11% yield). MP: 234-236° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 12.75(s,1H), 8.06(s,1H), 7.86-7.70(m,4H),7.61(s,1H), 7.33(m,2H), 7.06(dt, J=8.9,2.5 Hz, 1H), 6.87(m,2H), 6.07(q,J=7.0 Hz, 1H), 2.48(s,3H), 1.91(d, J=7.1 Hz, 3H). Mass: 549.95(M⁺).

Example 1092-(1-(4-amino-3-(2,3-dihydrobenzofuran-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 107 (0.100 g, 0.394 mmoles) in DMF (4 ml),potassium carbonate (0.109 g, 0.789 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 36 (0.217 g, 0.789 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.085g, 41% yield). MP: 238-241° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.04(s,1H), 8.02(d, J=6.0 Hz, 1H), 7.83(m,1H), 7.68(d, J=8.3 Hz, 1H),7.53(t, J=7.7 Hz, 1H), 7.44(s,1H), 7.31(m,3H), 7.05(t, J=8.9 Hz, 1H),6.90(m,2H), 6.01(q, J=7.0 Hz, 1H), 4.60(t, J=8.7 Hz, 2H), 3.27(t, J=8.6Hz, 2H), 1.88(d, J=7.0 Hz, 3H), Mass: 520.00(M⁺).

Example 1102-(1-(4-amino-3-(3-ethyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), N-Boc-3-ethyl-6-indazoleboronic acidpinacol ester 103 (0.423 g, 1.137 mmoles) and sodium carbonate (0.241 g,2.27 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as off-white solid (0.060 g, 15% yield). MP: 270-273° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 12.75(s,1H), 8.08(s,1H), 8.05(dd, J=7.9,1.4Hz, 1H), 7.88(m, 2H), 7.68(d, J=8.4 Hz, 1H), 7.63(s,1H), 7.53(d, J=7.2Hz, 1H), 7.33(d, J=8.3 Hz, 1H), 7.29(br s, 1H), 7.07(dt, J=8.9,1.4 Hz,1H), 6.95(br s,2H), 6.07(q, J=6.9 Hz, 1H), 2.98(q, J=7.5 Hz, 2H),1.92(d, J=7.1 Hz, 3H), 1.34(t, J=7.6 Hz, 3H), Mass: 546.04(M⁺).

Example 1112-(1-(4-amino-3-(3-methyl-1H-indol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), 3-methyl-6-indoleboronic acid pinacolester 106 (0.390 g, 1.517 mmoles) and sodium carbonate (0.241 g, 2.27mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as off-white solid (0.040 g, 10% yield). MP: 269-272° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 10.91(s,1H), 8.06(s,1H), 8.05(d, J=7.8 Hz,1H), 7.85(t, J=7.2 Hz, 1H), 7.68(d, J=8.4 Hz, 1H), 7.63(d, J=7.1 Hz,1H), 7.56(s,1H), 7.53(t, J=7.8 Hz, 1H), 7.25(d, J=8.1 Hz, 1H), 7.28(brs,1H), 7.21(s,1H), 7.06(dt, J=9.0,2.8 Hz, 1H), 6.98(br s,2H), 6.04(q,J=7.0 Hz, 1H), 2.28(s, 3H), 1.91(d, J=7.0 Hz, 3H). Mass: 530.99(M⁺).

Example 1122-(1-(4-amino-3-(2-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), 2-methoxypyrimidine-5-boronic acid(0.233 g, 1.517 mmoles) and sodium carbonate (0.241 g, 2.27 mmoles) wereadded and the system is degassed for 30 min. TetrakistriphenylphosphinePalladium (0.043 g, 0.037 mmoles) was added under nitrogen atmosphereand heated to 80° C. After 12 h, the reaction mixture was celitefiltered, concentrated and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as off-whitesolid (0.200 g, 51% yield). MP: 224-227° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): δ 8.72(s,2H), 8.09(s,1H), 8.04(dd, J=7.9,1.4 Hz, 1H), 7.84(m,1H),7.69(d, J=8.3 Hz, 1H), 7.52(t, J=7.8 Hz, 1H), 7.32(m,1H),7.12-6.95(m,5H), 6.03(q, J=7.1 Hz, 1H), 1.90(d, J=7.0 Hz, 3H). Mass:509.99(M⁺).

Example 1134-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2-carbaldehyde

To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (5 ml),ethanol (2.5 ml) and water (2.5 ml), 2-formyl-4-thiopheneboronic acid(0.155 g, 0.995 mmoles) and sodium carbonate (0.210 g, 1.98 mmoles) wereadded and the system is degassed for 30 min TetrakistriphenylphosphinePalladium (0.038 g, 0.033 mmoles) was added under nitrogen atmosphereand heated to 80° C. After 12 h, the reaction mixture was celitefiltered, concentrated and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as light brownsolid (0.065 g, 19% yield). MP: 192-195° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): δ 10.01(s,1H), 8.30(s,1H), 8.24(s,1H), 8.07(s,1H), 8.05(dd,J=7.9,1.4Hz, 1H), 7.85(m,1H),7.69(d, J=8.4Hz, 1H),7.53(t, J=7.8Hz,1H),7.28(br s,1H), 7.06(t, J=8.8Hz, 1H),6.93(br s, 2H), 6.04(q, J=7.0Hz, 1H),1.89(d, J=7.0 Hz, 3H). Mass: 511.95(M⁺).

Example 1142-(1-(4-amino-3-(5-(hydroxymethyl)thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.300 g, 0.568 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), 2-hydroxymethyl-4-thiopheneboronic acid(0.133 g, 0.853 mmoles) and sodium carbonate (0.180 g, 1.70 mmoles) wereadded and the system is degassed for 30 min TetrakistriphenylphosphinePalladium (0.033 g, 0.028 mmoles) was added under nitrogen atmosphereand heated to 80° C. After 12 h, the reaction mixture was celitefiltered, concentrated and extracted with ethyl acetate. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as light brownsolid (0.042 g, 14% yield). MP: 154-156° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): δ 8.05(s,1H), 8.04(dd, J=7.9,1.4 Hz, 1H), 7.85(m,1H), 7.67(d,J=6.4 Hz, 1H),7.66(s,1H), 7.53(t, J=7.2 Hz, 1H),7.29(br s,1H),7.20(s,1H), 7.06 (dt, J=8.8,2.1 Hz, 1H),6.98(br s, 2H), 6.02(q, J=6.9Hz, 1H),5.54(t, J=5.8 Hz, 1H),4.68(d, J=5.7 Hz, 2H), 1.88(d, J=7.0 Hz,3H). Mass: 514.19(M⁺+1).

Example 1152-(1-(4-amino-3-(2-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (5 ml),ethanol (2.5 ml) and water (2.5 ml), intermediate 109 (0.407 g, 1.137mmoles) and sodium carbonate (0.241 g, 2.274 mmoles) were added and thesystem is degassed for 30 min Tetrakistriphenylphosphine Palladium(0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heatedto 80° C. After 12 h, the reaction mixture was celite filtered,concentrated and extracted with ethyl acetate. The organic layer wasdried over sodium sulphate and concentrated under reduced pressure. Thecrude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as light brown solid (0.025g, 6% yield). MP: 154-156° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ12.34(s,1H),8.07(s,1H), 8.05(dd, J=7.9,1.3 Hz, 1H), 7.83(m,1H), 7.68(d,J=8.4 Hz, 1H), 7.62(m,2H), 7.53(t, J=7.3 Hz, 1H), 7.38-7.30(m, 3H),7.05(dt, J=8.5,1.9 Hz, 1H),6.93(br s, 1H), 6.05(q, J=6.9 Hz,1H),2.50(s,3H), 1.91(d, J=7.0 Hz, 3H). Mass: 531.97(M⁺).

Example 1162-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57g (0.400 g, 0.738 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), N-Boc-3-methyl-6-indazoleboronic acidpinacol ester 98 (0.397 g, 1.108 mmoles) and sodium carbonate (0.157 g,1.47 mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as off-white solid (0.023 g, 6% yield). MP: 268-270° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 12.75(s,1H), 8.07(s,1H), 8.04(dd, J=7.9,1.5Hz, 1H),7.86(m, 2H),7.69(d, J=8.2 Hz, 1H),7.64(s,1H), 7.53(t, J=7.9 Hz,1H),7.35(dd, J=8.2,1.4 Hz, 1H),7.33(br s,1H), 7.09(dt, J=8.9,2.2 Hz,1H), 6.90(br s,2H), 5.85(t, J=6.1 Hz, 1H),2.51(s,3H),2.50(m,2H), 0.82(t,J=7.3 Hz, 3H). Mass: 545.96 (M⁺).

Example 1172-(1-(4-amino-3-(3-methyl-1H-indol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57b (0.290 g, 0.583 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), 3-methyl-6-indoleboronic acid pinacolester 106 (0.299 g, 1.163 mmoles) and sodium carbonate (0.185 g, 1.749mmoles) were added and the system is degassed for 30 minTetrakistriphenylphosphine Palladium (0.033 g, 0.029 mmoles) was addedunder nitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as pale brown solid (0.014 g, 5% yield). MP: 262-265° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): δ 10.92(s,1H), 8.07(s,1H), 8.04(d, J=7.9 Hz,1H), 7.81(m, 1H),7.64(d, J=7.3 Hz, 1H),7.57(s,1H), 7.51(t, J=7.6 Hz,1H),7.35-7.10(m,7H), 5.97(q, J=7.0 Hz, 1H),2.28(s, 3H),1.91(d, J=7.0 Hz,3H). Mass: 512.99(M⁺).

Example 1182-((6-amino-9H-purin-9-yl)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of Adenine (0.162 g, 1.20 mmoles) in DMF (3.5 ml),potassium carbonate (0.165 g, 1.20 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 90 (0.200 g, 0.600 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.040 g,17% yield). MP: 207-209° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ8.09(s,1H), 8.07(s,1H), 7.73(dd, J=8.4,3.1 Hz, 1H), 7.66(dt, J=8.1,3.1Hz, 1H), 7.59(dd, J=9.1, 4.3 Hz, 1H), 7.45-7.40(m, 5H), 7.22(s,2H),5.34(s, 2H). Mass: 388.18(M⁺+1).

Example 1192-((6-amino-9H-purin-9-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Adenine (0.153 g, 1.13 mmoles) in DMF (3.5 ml),potassium carbonate (0.156 g, 1.13 mmoles) was added and stirred at RTfor 10 min. To this mixture intermediate 92 (0.200 g, 0.567 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as green solid (0.020 g, 9%yield). MP: 180-183° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.11(s, 1H),8.07(s, 1H), 7.73-7.65(m, 2H), 7.62(dd, J=9.2, 4.4 Hz, 1H), 7.50(q,J=7.9 Hz, 1H), 7.26(m, 5H), 5.36(s, 2H). Mass: 406.10(M⁺+1).

Example 1202-((4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 79 (0.110 g, 0.424 mmoles) in DMF (3 ml),N, N-diisopropylethylamine (0.109 g, 0.848 mmoles) was added and stirredat RT for 10 min. To this mixture, intermediate 92 (0.298 g, 0.848mmoles) was added and stirred for 12 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.075 g, 33% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.20(s, 1H),7.73-7.61(m, 3H), 7.38 (q, J=7.6 Hz, 1H), 7.17(m, 3H), 6.95(m, 3H),5.55(s, 2H), 3.82(s, 3H). Mass: 515.93 (M⁺).

Example 120a2-((4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 120 (0.075 g, 0.140 mmoles) in dichloromethane(10 ml), BBr₃ (1M in dichloromethane, 1.0 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as lightbrown solid (0.023 g, 31% yield). MP: 127-129° C. ¹H-NMR (δ ppm,DMSO-D₆, 400 MHz): δ 10.18(s,1H), 8.19(s, 1H), 7.74-7.61(m, 3H), 7.38(q,J=7.8 Hz, 1H),7.15(m,3H), 6.84(s,1H), 6.81(d, J=8.8 Hz, 1H), 6.65(d,J=10.8 Hz, 1H), 5.54(s, 2H). Mass: 515.54(M⁺).

Example 1212-(1-(4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 58 (0.254 g, 1.054 mmoles) in DMF (6 ml),potassium carbonate (0.331 g, 2.39 mmoles) was added and stirred at RTfor 10 min. To this mixture, intermediate 75 (0.350 g, 0.958 mmoles) wasadded and stirred for 12 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.210 g, 42% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.07(s,1H),7.82(dd, J=9.2,4.4 Hz, 1H), 7.76(dd, J=8.0,3.1 Hz, 1H), 7.72(dd,J=8.2,2.7 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H),7.28(br s, 1H), 7.18(d, J=7.7Hz, 1H), 7.10(t, J=2.4 Hz, 1H), 7.07(m, 2H), 6.92(m,2H), 6.04(q, J=7.0Hz, 1H), 3.80(s,3H)1.89(d, J=7.1 Hz, 3H).

Example 121a2-(1-(4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 121 (0.180 g, 0.324 mmoles) in dichloromethane(15 ml), BBr₃ (1M in dichloromethane, 1.6 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as greysolid (0.045 g, 27% yield). MP: 193-196° C. ¹H-NMR (δ ppm, DMSO-D₆, 400MHz): δ 9.74(s,1H), 8.17(s, 1H), 7.83-7.70(m, 4H), 7.63(m,1H), 7.35(t,J=8.2 Hz, 1H), 7.31(m,1H), 7.12(m,4H), 6.99(m, 2H), 6.08(q, J=6.8 Hz,1H), 1.90(d, J=7.0 Hz, 3H). Mass: 511.87(M⁺).

Example 122 2-((9H-purin-6-ylamino)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 73 (3.0 g, 12.03 mmoles) indichloromethane (30 ml), triethylamine (5.0 ml, 36.11 mmoles) was addedfollowed by N-Boc-Glycine (2.53 g, 14.44 mmoles). To this mixture HATU(9.15 g, 24.07 mmoles) was added and stirred at RT for 12 h. Thereaction mixture was quenched by the addition of water and extractedwith dichloromethane. The organic layer was dried over sodium sulphateand concentrated under reduced pressure. The crude product was purifiedby column chromatography with ethyl acetate: petroleum ether to affordthe isoflavone intermediate (4 g). To a solution of this intermediate(4.0 g), trifluoroacetic acid (4 ml) was added and stirred at RT for 2h. The reaction mixture was concentrated, basified with sodiumbicarbonate solution, extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated under reduced pressureto afford the amine intermediate (2.5 g). To a solution of this amineintermediate (0.500 g, 1.74 mmoles) in tert-butanol (8 ml),N,N-diisopropylethylamine (0.6 ml, 2.94 mmoles) and 6-chloropurine(0.268 g, 1.74 mmoles) were added and refluxed for 24 h. The reactionmixture was concentrated, diluted with water, extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as pale brown solid (0.090 g, 13% yield). MP: 229-232° C.¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 12.97(s,1H), 8.15(m,1H), 8.13(s,1H),8.11(s,1H), 7.73(dd, J=8.4,3.1 Hz, 1H), 7.68(m,2H), 7.46(q, J=6.4 Hz),7.26-7.20(m,3H), 4.60 (br s, 2H). Mass: 406.17(M⁺+1).

Example 123 2-((9H-purin-6-ylamino)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of intermediate 50 (3.0 g, 13.03 mmoles) indichloromethane (30 ml), triethylamine (5.4 ml, 39.09 mmoles) was addedfollowed by N-Boc-Glycine (2.73 g, 15.63 mmoles). To this mixture HATU(9.90 g, 26.08 mmoles) was added and stirred at RT for 12 h. Thereaction mixture was quenched by the addition of water and extractedwith dichloromethane. The organic layer was dried over sodium sulphateand concentrated under reduced pressure. The crude product was purifiedby column chromatography with ethyl acetate: petroleum ether to affordthe isoflavone intermediate (2.5 g). To a solution of this intermediate(2.5 g), trifluoroacetic acid (3 ml) was added and stirred at RT for 2h. The reaction mixture was concentrated, basified with sodiumbicarbonate solution, extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated under reduced pressureto afford the amine intermediate (1.7 g). To a solution of this amineintermediate (0.500 g, 1.85 mmoles) in tert-butanol (8 ml),N,N-diisopropylethylamine (0.64 ml, 3.71 mmoles) and 6-chloropurine(0.286 g, 1.85 mmoles) were added and refluxed for 24 h. The reactionmixture was concentrated, diluted with water, extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as pale brown solid (0.070 g, 10% yield). MP: 183-186° C.¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 12.96(s,1H), 8.16(m, 1H),8.14(s,1H), 8.11(s,1H), 7.73(dd, J=8.4,3.1 Hz, 1H), 7.67(m,2H),7.45-7.35(m,5H), 4.59 (br s, 2H). Mass: 388.25 (M⁺+1).

Example 124 (R)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 73 (3.0 g, 12.03 mmoles) indichloromethane (30 ml), triethylamine (5.0 ml, 36.11 mmoles) was addedfollowed by N-Boc-D-Alanine (2.70 g, 14.44 mmoles). To this mixture HATU(9.15 g, 24.07 mmoles) was added and stirred at RT for 12 h. Thereaction mixture was quenched by the addition of water and extractedwith dichloromethane. The organic layer was dried over sodium sulphateand concentrated under reduced pressure. The crude product was purifiedby column chromatography with ethyl acetate: petroleum ether to affordthe isoflavone intermediate (1.8 g). To a solution of this intermediate(1.8 g), trifluoroacetic acid (1.8 ml) was added and stirred at RT for 2h. The reaction mixture was concentrated, basified with sodiumbicarbonate solution, extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated under reduced pressureto afford the amine intermediate (1.1 g). To a solution of this amineintermediate (1.0 g, 3.31 mmoles) in tert-butanol (20 ml),N,N-diisopropylethylamine (1.15 ml, 6.63 mmoles) and 6-chloropurine(0.384 g, 2.48 mmoles) were added and refluxed for 24 h. The reactionmixture was concentrated, diluted with water, extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: ethyl acetate to afford the titlecompound as pale brown solid (0.100 g, 7% yield). MP: 194-197° C. ¹H-NMR(δ ppm, DMSO-D₆, 400 MHz): δ 12.96(s, 1H), 8.14(m, 3H), 7.70(m, 3H),7.49(q, J=7.3 Hz, 1H), 7.25(m, 3H), 5.20(br s, 1H), 1.55 (d, J=6.9 Hz,3H). Mass: 419.96 (M⁺).

Example 1252-((4-amino-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one

To a solution of intermediate 57d (0.400 g, 0.77 mmoles) in DMF (5 ml),ethanol (2.5 ml) and water (2.5 ml), N-Boc-pyrazole-4-boronic acidpinacol ester (0.344 g, 1.16 mmoles) and sodium carbonate (0.165 g, 1.16mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine. Palladium (0.027 g, 0.023 mmoles) was added undernitrogen atmosphere and heated to 80° C. After 12 h, the reactionmixture was celite filtered, concentrated and extracted with ethylacetate. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as yellow solid (0.120 g, 34% yield). MP: 211-214° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 13.19(s,1H), 8.19(s,1H), 8.10(s,1H),7.79(s,1H), 7.73(dd, J=8.3, 3.1 Hz, 1H),7.71(dt, J=8.7.5,3.1 Hz, 1H),7.54(dd, J=9.3,4.3 Hz, 1H), 7.40-7.20(m, 5H), 6.92(br s, 2H), 5.46(s,2H). Mass: 454.26(M⁺).

Example 1262-(1-(4-amino-3-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 113 (0.110 g, 0.396 mmoles) in DMF (10ml), cesium carbonate (0.258 g, 0.792 mmoles) was added and stirred atRT for 10 min. To this mixture, intermediate 36 (0.275 g, 0.792 mmoles)was added and stirred for 12 h. The reaction mixture was diluted withwater and extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.122 g,56% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.07(s,1H), 8.04(dd,J=7.9,1.5 Hz, 1H), 7.85(m, 1H), 7.68(dd, J=8.3 Hz, 1H), 7.63(m, 1H),7.56(m,2H), 7.35(s, 1H), 7.30(d, J=8.7 Hz, 2H), 7.07(dt, J=8.7,2.3 Hz,1H), 6.93(br s,2H), 6.04(q, J=6.9 Hz, 1H), 3.97(s,3H), 1.88 (d, J=7.0Hz, 3H).

Example 126a2-(1-(4-amino-3-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of example 126 (0.122 g, 0.224 mmoles) in dichloromethane(10 ml), BBr₃ (1M in dichloromethane, 1.2 ml) was added at 0° C. and thereaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated to afford the title compound as brown solid (0.086 g, 72%yield). MP: 253-257° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 9.64(s,1H),8.05(s,1H), 8.04(dd, J=8.0,1.4 Hz, 1H), 7.83(m,1H), 7.68(d, J=8.4 Hz,1H), 7.52(t, J=5.3 Hz, 1H), 7.30(m,1H), 7.20(d, J=8.7 Hz, 2H), 7.06(dt,J=8.7,2.2 Hz, 1H), 6.98(br s, 2H), 6.00(q, J=7.0 Hz, 1H), 1.88(d, J=7.0Hz, 3H). Mass: 5530.14(M⁺+1).

Example 1272-((4-amino-3-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 113 (0.080 g, 0.288 mmoles) in DMF (3 ml),N,N-diisopropylethylamine (0.074 g, 0.577 mmoles) was added and stirredat RT for 10 min. To this mixture, intermediate 92 (0.203 g, 0.577mmoles) was added and stirred for 12 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.109 g,68% yield). ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 8.20(s, 1H),7.73-7.52(m, 4H), 7.38(m, 1H), 7.30(d, J=8.8 Hz, 2H), 7.16-7.07(m, 4H),5.53(s, 2H), 3.96(s, 3H).

Example 127a2-((4-amino-3-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of example 127 (0.099 g, 0.180 mmoles) in dichloromethane(10 ml), BBr₃ (1M in dichloromethane, 0.99 ml) was added at 0° C. andthe reaction mixture was warmed to RT and then stirred for 12 h. Thereaction mixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated to afford the title compound as brown solid (0.022 g, 23%yield). MP: 274-278° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ 10.20(s,1H), δ 8.18(s, 1H), 7.72-7.60(m, 4H), 7.38(m, 1H), 7.20 (d, J=8.7 Hz,2H), 7.17-7.10(m, 4H), 5.51(s, 2H). Mass: 534.06(M⁺+1).

Example 128(+)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-oneExample 129(−)-2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The two enantiomerically pure isomers were obtained by preparativechiral hplc separation from example 79 on a CHIRALPAK IA column (250×20mm; 5μ) using dichloromethane: acetonitrile:methanol (90:08:02, v/v/v)as the mobile phase.

(+)-Isomer: Off-white solid, e.e. 99.68%. Rt: 5.55 min (CHIRALPAK IA,conditions as above). MP: 158-161° C. [α]²⁵ _(D) 196.56 (c=0.40,CH₂Cl₂). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 12.74 (s,1H), 8.08 (s,1H),8.05 (dd, J=7.9,1.4 Hz, 1H), 7.86 (m, 2H), 7.68 (d, J=8.4 Hz, 1H),7.62(s,1H), 7.53(t, J=7.8 Hz, 1H),7.34(d, J=8.3 Hz, 1H), 7.31(m, 1H),7.07(dt, J=8.8,2.3 Hz, 1H), 6.93(br s, 2H), 6.07(q, J=7.0 Hz, 1H),2.51(s,3H), 1.92 (d, J=7.1 Hz, 3H). Mass: 532.39(M⁺+1).

(−)-Isomer: Off-white solid, e.e.98.33%. Rt: 7.39 min (CHIRALPAK IA,conditions as above). MP: 157-160° C. [α]²⁵ _(D) −191.54 (c=0.40,CH₂Cl₂). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 12.75(s,1H), 8.08(s,1H),8.05(dd, J=7.9,1.4 Hz, 1H), 7.85(m, 2H), 7.68(d, J=8.4 Hz, 1H),7.62(s,1H), 7.53(t, J=7.9 Hz, 1H),7.34(dd, J=8.3,1.1 Hz, 1H), 7.31(m,1H), 7.07(dt, J=8.6,2.1 Hz, 1H), 6.94(br s, 2H), 6.07(q, J=6.9 Hz, 1H),2.51(s,3H), 1.92(d, J=7.1 Hz, 3H). Mass: 532.39(M⁺+1).

Example 1302-(1-(4-amino-3-(3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of example 57c (100 mg, 0.190 mmol) in DME (1 ml), andwater (0.5 ml), 3,5-dimethoxy phenyl boronic acid (0.209 mmol) andsodium carbonate (40 mg, 0.380 mmol) were added and the system wasdegassed for 5 min1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.8 mg,0.038 mmol) was added under nitrogen atmosphere and the mixture washeated to 90° C. at a microwave reactor for 15 min LC-MS analysisindicated the total consumption of example 57c, then ethyl acetate (2ml) and water (0.5 ml) was added. The two phases were separated and theaqueous layer was extracted by ethyl acetate (1 ml). The combinedorganic layer was dried over Na₂SO₄, filtered and evaporated to dryness.The residue was purified by preparative TLC using mixture of ethylacetate: petroleum ether in 2:1 ratio as an eluent to afford the desiredcompound. Brown solid (23.4 mg, 23%). MP: 224-227° C. ¹H-NMR (δ ppm,CDCl₃, 300 MHz): δ 8.24(s,1H), 8.21(dd, J=8.0,1.5 Hz, 1H), 7.69(m,1H),7.48(d, J=8.4 Hz, 1H), 7.42(t, J=8.0 Hz, 1H), 7.32(m,1H), 7.04(m,3H),6.79(d, J=2.3 Hz, 2H), 6.56(t, J=2.1 Hz, 1H), 6.11(q, J=7.2 Hz, 1H),5.58(s,2H), 3.85(s, 6H), 2.02(d, J=7.1 Hz, 3H). Mass: 537.8(M+).

Example 1312-(1-(4-amino-3-(4-methoxy-3,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3,5-dimethyl-4-methoxyphenyl boronic acid (0.209 mmol). Brown solid(20 mg, 20%). MP: 234-236° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ8.22(s,1H), 8.21(dd, J=8.0,1.5 Hz, 1H), 7.69(m,1H), 7.48(d, J=8.4 Hz,1H), 7.42(t, J=8.0 Hz, 1H), 7.30(s,2H), 7.29(m,1H), 7.02-6.95(m, 3H),6.10(q, J=7.1 Hz,1H), 5.43(s,2H), 3.77(s, 3H), 2.36(s,6H), 2.01(d, J=7.1Hz, 3H). Mass: 535.9(M+).

Example 1322-(1-(4-amino-3-(2-fluoro-5-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 2-Fluoro-5-isopropoxyphenyl boronic acid (0.209 mmol). Brown solid(50.6 mg, 48%). MP: 198-201° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ8.24(s,1H), 8.21(dd, J=7.9,1.5 Hz, 1H), 7.68(m,1H), 7.47(d, J=8.0 Hz,1H), 7.41(dd, J=8.0,0.9 Hz, 1H), 7.34(m,1H), 7.18(t, J=9.9 Hz, 1H),7.07-6.96(m, 5H), 6.13(q, J=7.1 Hz, 1H), 5.32(s,2H), 4.53 (quintet,J=6.0 Hz, 1H), 2.01(d, J=7.1 Hz, 3H), 1.35(d, J=6.0 Hz, 6H). Mass:553.8(M+).

Example 1332-(1-(4-amino-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid (or boronicacid pinacol ester) was replaced by-2,3-dihydrobenzo[b][1,4]dioxin-6-ylboronic acid (0.209 mmol) Off-whitesolid (22 mg, 22%). MP: 225-226° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ8.21(s,1H), 8.19(dd, J=8.1,1.2 Hz, 1H), 7.69(m,1H), 7.48(d, J=8.4 Hz,1H), 7.42(dt, J=8.1,1.2 Hz, 1H), 7.31(m,1H), 7.19(d, J=2.1 Hz, 1H),7.15(dd, J=8.4,2.1 Hz, 1H), 7.03-6.95(m,4H), 6.09(q, J=7.2 Hz, 1H),5.58(s,2H), 4.31(s,4H), 2.00(d, J=7.2 Hz, 3H). Mass: 535.8(M+).

Example 1342-(1-(4-amino-3-(1-benzyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid (or boronicacid pinacol ester) was replaced by -1-benzylpyrazole-4-boronic acidpinacol ester (0.209 mmol) Brown solid (35 mg, 33%). MP: 140-142° C.¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.21(s,1H), 8.21(dd, J=8.2,1.5 Hz,1H), 7.84(s,1H), 7.73(s,1H), 7.67(m, 1H), 7.47(d, J=8.2 Hz, 1H),7.40-7.32(m, 7H), 6.98(m,3H), 6.05(q, J=7.2 Hz,1H), 5.41(s,2H), 5.38(s,2H), 1.98(d, J=7.1 Hz, 3H). Mass: 557.8(M+).

Example 1352-(1-(4-amino-3-(2-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 2-methylpyridine-4-boronic acid (0.209 mmol) Off-white solid (30 mg,32%). MP: 266-268° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ), 8.68(d, J=5.4Hz, 1H), 8.27(s,1H), 8.22(dd, J=7.9,1.5 Hz, 1H), 7.70(m,1H),7.49-7.32(m,5H), 7.04-6.92(m,3H), 6.13(q, J=7.2 Hz, 1H), 5.47(s,2H),2.67(s, 3H), 2.02(d, J=7.2 Hz, 3H). Mass: 492.8(M+).

Example 1362-(1-(4-amino-3-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (0.209 mmol)Brown solid (15 mg, 14%). MP: 234-237° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): δ 8.22(s,1H), 8.19(dd, J=7.5,1.8 Hz, 1H), 7.69(m,1H), 7.48(d,J=8.4 Hz, 1H), 7.43(dt, J=7.8,0.9 Hz, 1H), 7.30(d, J=2.1 Hz, 1H),7.28(m,2H), 7.23(d, J=2.1 Hz, 1H), 7.20(m,3H), 6.10(q, J=7.2 Hz,1H),5.62(s,2H), 4.31(d, J=5.7 Hz, 4H),2.27(t, J=5.7 Hz, 2H), 2.01(d, J=7.2Hz, 3H). Mass: 549.5(M+).

Example 1372-(1-(4-amino-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 6-morpholinopyridin-3-ylboronic acid (0.209 mmol) Brown solid (36 mg,34%). MP: 269-271° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.49(d, J=2.1Hz, 1H), 8.24(s,1H), 8.21(dd, J=8.0,1.5 Hz, 1H), 7.82(dd, J=8.8,2.4 Hz,1H), 7.69(m,1H), 7.48(d, J=8.4 Hz, 1H), 7.42(t, J=8.0 Hz, 1H), 7.30(m,1H), 7.02-6.91(m,3H), 6.77(d, J=8.8 Hz, 1H), 6.12(q, J=7.2 Hz, 1H),5.41(s,2H), 3.86(t, J=4.6 Hz, 4H), 3.61(t, J=5.0 Hz, 4H), 2.01(d, J=7.1Hz, 3H). Mass: 563.8(M+).

Example 1382-(1-(4-amino-3-(dibenzo[b,d]furan-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby—dibenzo[b,d]furan-4-ylboronic acid (0.209 mmol) Brown solid (52.6 mg,49%). MP: 238-240° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.28(s,1H),8.23(d, J=6.7 Hz, 1H), 8.10(d, J=7.1 Hz, 1H), 8.03(d, J=7.6 Hz, 1H),7.71(m,2H), 7.54-7.49(m,4H), 7.46(t, J=7.6 Hz, 2H), 7.34(m,1H), 7.11(d,J=7.6 Hz, 1H), 7.06(m, 2H), 6.20(q, J=7.1 Hz, 1H), 5.29(s,2H), 2.07 (d,J=7.1 Hz, 3H). Mass: 567.8(M+).

Example 1392-(1-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 4-phenoxyphenylboronic acid (0.209 mmol) Brown solid (61.9 mg, 57%).MP: 218-220° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.24(s,1H), 8.22(dd,J=7.9,1.5 Hz, 1H), 7.69(m,3H), 7.42(d, J=8.2 Hz, 1H), 7.41(m,3H),7.32(m,1H), 7.19-7.13(m,3H), 7.08-6.92(m,5H), 6.11(q, J=7.1 Hz, 1H),5.39(s,2H), 2.02(d, J=7.2 Hz, 3H). Mass: 569.8(M+).

Example 1402-(1-(4-amino-3-(4-(benzyloxy)-3-chlorophenol)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 4-(benzyloxy)-3-chlorophenylboronic acid (0.209 mmol) Brown solid (58mg, 49%). MP: 214-216° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.24(s,1H),8.22(dd, J=7.9,1.5 Hz, 1H), 7.74(d, J=2.1 Hz, 1H), 7.69(m,1H),7.49-7.31(m,9H), 7.12 (d, J=8.5 Hz, 1H), 7.03(m,2H), 6.94(d, J=9.3 Hz,1H), 6.10(q, J=7.2 Hz, 1H), 5.38(s,2H), 5.24(s,2H), 2.00(d, J=7.1 Hz,3H). Mass: 618.8(M+).

Example 1412-(1-(4-amino-3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby -3-chloro-4-isopropoxyphenylboronic acid (0.209 mmol) Brown solid(52.8 mg, 49%). MP: 198-200° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ8.24(s,1H), 8.22(dd, J=8.0,1.5 Hz, 1H), 7.70(m,2H), 7.51-7.47(m,2H),7.42(dt, J=8.0,0.9 Hz, 1H), 7.30(m,1H), 7.09(d, J=7.5 Hz, 1H),7.03-6.91(m,3H), 6.12(q, J=7.1 Hz,1H), 5.41(s,2H), 4.67(quintet, J=6.2Hz, 1H), 2.01(d, J=7.1 Hz, 3H), 1.44(d, J=6.0 Hz, 6H). Mass: 570.8(M+).

Example 142 2-(1-(4-amino-3-(3-(dimethylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby -3-(dimethylamino)phenylboronic acid (0.209 mmol) Brown solid (60 mg,60%). MP: 218-220° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.23(s,1H),8.21(dd, J=8.0,1.5 Hz, 1H), 7.68(m,1H), 7.48(d, J=8.2 Hz, 1H),7.41(m,2H), 7.35(m,1H), 7.05(d, J=7.6 Hz, 1H), 7.01-6.95(m,4H), 6.83(dd,J=8.7,2.1 Hz, 1H), 6.11(q, J=7.1 Hz,1H), 5.52(s,2H), 3.01(s,6H), 2.02(d,J=7.1 Hz, 3H). Mass: 520.8(M+).

Example 1432-(1-(4-amino-3-(4-ethoxy-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic was replaced by4-ethoxy-3-fluorophenylboronic acid (0.209 mmol) Brown solid (47.5 mg,46%). MP: 216-218° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.24(s,1H),8.22(dd, J=8.1,1.5 Hz, 1H), 7.68(m,1H), 7.49-7.35(m,5H), 7.13(t, J=8.4Hz, 1H), 7.07(m, 3H), 6.10(q, J=7.2 Hz, 1H), 5.50(s,2H), 4.19(q, J=7.2Hz, 2H),2.01(d, J=7.2 Hz, 3H), 1.52(t, J=7.2 Hz, 3H). Mass: 539.8(M+).MS DATA

Example 1442-(1-(4-amino-3-(4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby -4-isopropoxyphenylboronic acid (0.209 mmol) Brown solid (23.2 mg,23%). MP: 224-226° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.22(s,1H),8.22(dd, J=8.0,1.5 Hz, 1H), 7.67(m,1H), 7.58(dd, J=6.7,1.9 Hz, 2H),7.49(d, J=8.3 Hz, 1H), 7.42(dt, J=8.0,1.0 Hz, 1H), 7.30(m,1H),7.04-6.98(m,5H), 6.12(q, J=7.1 Hz,1H), 5.41(s,2H), 4.65(quintet, J=6.1Hz, 1H),2.01(d, J=7.1 Hz, 3H), 1.38(d, J=6.0 Hz, 6H). Mass: 535.8(M+).

Example 1452-(1-(4-amino-3-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 4-(trifluoromethoxy)phenylboronic acid (0.209 mmol) Brown solid (46.6mg, 48%). MP: 224-226° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.26(s,1H),8.22(dd, J=7.9,1.5 Hz, 1H), 7.74(d, J=7.6 Hz, 2H), 7.70(m,1H), 7.48(d,J=8.3 Hz, 1H), 7.42(m, 1H), 7.40(d, J=8.1 Hz, 2H), 7.33(m,1H),7.04(m,2H), 6.93(d, J=7.9 Hz, 2H), 6.12(q, J=7.2 Hz, 1H), 5.39(s,2H),2.02(d, J=7.2 Hz, 3H). Mass: 561.8(M+).

Example 1462-(1-(3-(4-acetylphenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 4-acetylphenylboronic acid (0.209 mmol) Off-white solid (20 mg, 20%).MP: 218-221° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.26(s,1H), 8.22(dd,J=7.9,1.5 Hz, 1H), 8.13(d, J=8.3 Hz, 2H), 7.82(d, J=8.4 Hz, 2H),7.70(m,1H), 7.48(d, J=8.2 Hz, 1H), 7.43(dt, J=8.0,0.9 Hz, 1H),7.31(m,1H), 7.04-6.92(m,3H), 6.13(q, J=7.1 Hz, 1H), 5.47(s,2H),2.67(s,3H), 2.03(d, J=7.2 Hz, 3H). Mass: 519.8(M+).

Example 1472-(1-(4-amino-3-(4-(benzyloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 4-(benzyloxy)phenylboronic acid (0.209 mmol) Off-white solid (68.2mg, 61%). MP: 176-178° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.22(s,1H),8.22(dd, J=9.0,1.6 Hz, 1H), 7.69(m,1H), 7.48-7.23(m,11H),7.12-6.92(m,4H), 6.12(q, J=7.1 Hz,1H), 5.37(s,2H), 5.16(s,2H), 2.01 (d,J=7.1 Hz, 3H). Mass: 583.9(M+).

Example 148 2-(1-(4-amino-3-(4-(dimethylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 4-(dimethylamino)phenylboronic acid (0.209 mmol) Brown solid (12.6mg, 13%). MP: 214-217° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.21(dd,J=7.8,1.6 Hz, 1H), 8.21(s,1H), 7.69(m,1H), 7.54-7.48(m,3H), 7.41(dt,J=8.0,0.9 Hz, 1H), 7.31(m,1H), 7.02-6.95(m,3H), 6.84(d, J=8.8 Hz, 2H),6.09(q, J=7.1 Hz,1H), 5.47(s,2H), 3.02(s,6H), 2.01(d, J=7.2 Hz, 3H).Mass: 520.89(M+).

Example 1492-(1-(4-amino-3-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 4-(methylsulfonyl) phenylboronic acid (0.209 mmol). Off-white solid(48.9 mg, 46%). MP: 259-262° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ8.27(s,1H), 8.22(dd, J=8.0,1.5 Hz, 1H), 8.14(d, J=8.5 Hz, 2H), 7.93(d,J=8.5 Hz, 2H), 7.69(m,1H), 7.47(d, J=8.2 Hz, 1H), 7.43(dt, J=8.0,1.0 Hz,1H), 7.32(m,1H), 7.03-6.90(m,3H), 6.16(q, J=7.1 Hz, 1H), 5.56(s,2H),3.12(s,3H), 2.02(d, J=7.1 Hz, 3H). Mass: 555.8(M+).

Example 1502-(1-(4-amino-3-(3-ethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3-ethoxyphenylboronic acid (0.209 mmol) Off-white solid (42.6 mg,43%). MP: 162-165° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.15(m,2H),7.38(t, J=7.5 Hz, 1H), 7.18(m,3H), 7.11(m,3H), 6.95(m,4H), 6.04(q, J=7.0Hz, 1H), 5.63(s,2H), 4.03(q, J=7.2 Hz, 2H), 1.95(d, J=6.9 Hz,3H),1.39(t, J=7.2 Hz, 3H). Mass 521.8(M+).

Example 1512-(1-(4-amino-3-(benzo[b]thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby -benzo[b]thiophen-2-ylboronic acid (0.209 mmol) Brown solid (25 mg,24%). MP: 242-245° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.30-8.20(m,2H), 7.91(m, 2H), 7.69(m, 2H), 7.50-7.25(m, 5H), 7.07(m, 3H), 6.12(q,J=7.1 Hz, 1H), 5.77(s, 2H), 2.04(d, J=7.2 Hz, 3H). Mass 533.8(M+).

Example 1522-(1-(4-amino-3-(5-chlorothiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 5-chlorothiophen-2-ylboronic acid (0.209 mmol) Brown solid (14.5 mg,15%). MP: 226-229° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.25(s,1H),8.21(dd, J=8.0,1.5 Hz, 1H), 7.70(m,1H), 7.48(d, J=8.2 z, 1H), 7.42(dt,J=8.0,1.1 Hz, 1H), 7.34(m,1H), 7.16(dt, J=3.8 Hz, 1H),7.04(m,3H),6.96(d, J=9.3 Hz, 1H), 6.08(q, J=7.1 Hz,1H), 5.62(s,2H),2.00(d, J=7.1 Hz, 3H). Mass: 517.88(M+)

Example 1532-(1-(4-amino-3-(3,5-dimethylisoxazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3,5-dimethylisoxazol-4-ylboronic acid (0.209 mmol) Brown solid (23.1mg, 24%). MP: 218-222° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.27(s,1H),8.22(dd, J=8.5,1.6 Hz, 1H), 7.69(m,1H), 7.42(m, 3H), 7.11-6.99(m,3H),6.12(q, J=7.2 Hz, 1H), 5.21(s,2H), 2.44(s,3H), 2.29(s,3H), 1.99(d, J=7.2Hz, 3H). Mass: 496.9(M+).

Example 1542-(1-(4-amino-3-(3-propoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic was replaced by3-propoxyphenylboronic acid (0.209 mmol) Brown solid (65.4 mg, 64%). MP:178-182° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.24(s,1H), 8.22(dd,J=8.0,1.6 Hz, 1H), 7.69(m,1H), 7.48-7.38(m,3H), 7.31(m,1H), 7.23(m,2H),7.04-6.93(m,4H), 6.13(q, J=7.2 Hz, 1H), 5.47(s,2H), 4.00(t, J=6.6 Hz,2H), 2.02(d, J=7.1 Hz, 3H),1.86(m,2H), 1.07(t, J=7.4 Hz, 3H). Mass:535.8(M+).

Example 1552-(1-(4-amino-3-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby -furan-2-ylboronic acid (0.209 mmol) Brown solid (24.6 mg, 28%). MP:234-236° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.22(s,1H), 8.19(dd,J=8.3,1.7 Hz, 1H), 7.68(m,1H), 7.59(d, J=1.5 Hz, 1H), 7.49(t, J=6.8 Hz,1H), 7.40(t, J=7.4 Hz, 1H), 7.31(m,1H), 6.99-6.96(m,4H), 6.61(q, J=1.7Hz, 1H), 6.07(q, J=7.2 Hz,1H), 1.99(d, J=7.2 Hz, 3H. Mass: 467.9(M+).

Example 1562-(1-(4-amino-3-(4-ethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic was replaced by4-ethoxyphenylboronic acid (0.209 mmol). Brown solid (53.4 mg, 54%). MP:229-232° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.22(s,1H), 8.22(d, J=7.8Hz, 1H), 7.68(m,1H), 7.59(d, J=8.7 Hz, 2H), 7.49(d, J=8.4 Hz, 1H),7.40(m,2H), 7.06(m,5H), 6.11(q, J=7.2 Hz, 1H), 5.62(s,2H), 4.11(q, J=7.2Hz, 2H), 2.02(d, J=7.2 Hz, 3H),1.48(t, J=7.2 Hz, 3H). Mass: 521.9(M+).

Example 1572-(1-(4-amino-3-(3-chloro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid (or boronicacid pinacol ester) was replaced by 3-chloro-4-methoxyphenylboronic acid(0.209 mmol) Brown solid (30 mg, 29%,). MP: 246-249° C. ¹H-NMR (δ ppm,CDCl₃, 300 MHz): δ 8.24(s,1H), 8.22(dd, J=8.0,1.5 Hz, 1H),7.72-7.65(m,2H), 7.55(dd, J=8.4,2.1 Hz, 1H), 7.49(d, J=8.3 Hz, 1H),7.42(dt, J=8.0,0.9 Hz, 1H), 7.32(m,1H), 7.09(d, J=8.5 Hz, 1H),7.04(m,2H), 6.93(d, J=8.1 Hz, 1H), 6.12(q, J=7.3 Hz, 1H), 5.38(s,2H),3.98(s, 3H), 2.01(d, J=7.1 Hz, 3H). Mass: 541.8 M+).

Example 1582-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3-fluoro-4-isopropoxyphenylboronic acid (0.209 mmol) Brown solid (23mg, 22%). MP: 218-221° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.24(s,1H),8.22(dd, J=8.0,1.5 Hz, 1H), 7.70(m,1H), 7.49(d, J=8.2 Hz, 1H),7.44-7.30(m,4H), 7.14(d, J=8.4 Hz, 1H), 7.03-6.91(m,3H), 6.12(q, J=7.0Hz, 1H), 5.43(s,2H), 4.66(quintet, J=6.2 Hz, 1H), 2.00(d, J=7.1 Hz, 3H)1.42(d, J=6.1 Hz, 6H). Mass: 553.8(M+).

Example 1592-(1-(4-amino-3-(6-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 6-fluoropyridin-3-ylboronic acid (0.209 mmol) Brown solid (56.6 mg,60%). MP: 203-206° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.57(d, J=1.9Hz, 1H), 8.28(s,1H), 8.22(dd, J=7.9,1.4 Hz, 1H), 8.16(dt, J=7.9,2.4 Hz,1H), 7.70(m,1H), 7.47(d, J=8.3 Hz, 1H), 7.43(t, J=7.9 Hz, 1H),7.34(m,1H), 7.15(dd, J=8.4,2.8 Hz, 1H), 7.04(m, 2H), 6.93(d, J=7.8 Hz,1H), 6.13(q, J=7.1 Hz, 1H), 5.38(s,2H), 2.02(d, J=7.1 Hz, 3H). -Mass:496.9(M+).

Example 1602-(1-(4-amino-3-(pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic was replaced bypyrimidin-5-ylboronic acid (0.209 mmol) Brown solid (34 mg, 37%). MP:207-211° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 9.35(s,1H), 9.11(s,2H),8.32(s,1H), 8.22(dd, J=8.0,1.5 Hz, 1H), 7.69(m,1H), 7.48(d, J=8.4 Hz,1H), 7.43(t, J=8.0 Hz, 1H), 7.35(m,1H), 7.06(m,2H), 6.95(d, J=9.9 Hz,1H), 6.15(q, J=7.1 Hz, 1H), 5.31(s,2H), 2.03(d, J=7.1 Hz, 3H). Mass:479.9(M+).

Example 1612-(1-(4-amino-3-(3-(methoxymethyl)Phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3-(methoxymethyl)phenylboronic acid (0.209 mmol) Brown solid (60.5mg, 61%). MP: 167-170° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.27(m,2H),7.69-7.23(m,8H), 7.04-6.94(m,3H), 6.12(q, J=7.0 Hz, 1H), 5.41 (s,2H),3.48(s,3H), 2.02(d, J=7.2 Hz, 3H). Mass: 521.9(M+).

Example 1622-(1-(4-amino-3-(6-hydroxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 6-hydroxynaphthalen-2-ylboronic acid (0.209 mmol) Brown solid (32 mg,31%). MP: 281-285° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.26(s,1H),8.22(dd, J=9.1,1.4 Hz, 1H), 8.04(s,1H), 7.81(d, J=8.5 Hz, 2H),7.72-7.65(m,2H), 7.51(d, J=8.4 Hz, 1H), 7.42(dt, J=8.0,0.9 Hz, 1H),7.32(m,1H), 7.19(m,2H), 7.05(d, J=7.5 Hz, 1H), 6.16(q, J=7.1 Hz, 1H),5.46(s,2H), 2.05(d, J=7.1 Hz, 3H). Mass: 543.8(M+).

Example 1632-(1-(4-amino-3-(3-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3-isopropoxyphenylboronic acid (0.209 mmol) Off-white solid (65 mg,64%). MP: 153-157° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.24(s,1H),8.22(dd, J=8.0,1.5 Hz, 1H), 7.69(m,1H), 7.48(d, J=8.2 Hz, 1H),7.44(m,2H), 7.30(m,1H), 7.21(m,2H), 7.04-6.93(m,4H), 6.11(q, J=7.1 Hz,1H), 5.46(s,2H), 4.63(quintet, J=6.1 Hz, 1H), 2.02(d, J=7.1 Hz, 3H),1.37(d, J=6.1 Hz, 6H). Mass: 535.9(M+).

Example 1642-(1-(4-amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid (or boronicacid pinacol ester) was replaced by -1-methyl-1H-pyrazol-4-ylboronicacid pinacol ester (0.209 mmol) Yellow semi solid (30 mg, 33%). ¹H-NMR(δ ppm, CDCl₃, 300 MHz): δ 8.21(dd, J=8.0,1.4 Hz, 1H), 8.18(s,1H),7.78(s,1H), 7.73(s,1H), 7.69(m,1H), 7.48(d, J=8.1 Hz, 1H), 7.42(dt,J=7.1,1.8 Hz, 1H), 7.32(m,1H), 7.00-6.93(M,3H), 6.06(q, J=7.1 Hz, 1H),5.54(d, J=1.3 Hz, 2H), 4.00(s, 3H), 2.01(d, J=7.2 Hz, 3H). Mass:481.9(M+).

Example 1656-Fluoro-3-(3-fluorophenyl)-2-(1-(4-methoxyphenylamino)ethyl)-4H-chromen-4-one

To a solution of 4-methoxyaniline (0.201 g, 1.637 mmoles) in DMF (5 ml),N,N-diisopropylethylamine (0.158 g, 1.22 mmoles) was added and stirredat RT for 10 min. To this mixture intermediate 75 (0.300 g, 0.818mmoles) was added and stirred for 12 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with ethyl acetate 1:petroleum ether to afford the title compound as brown solid (0.105 g,31% yield). MP: 152-156° C. ¹H-NMR (δ ppm, DMSO-D₆, 400 MHz): δ7.73-7.66 (m,3H), 7.58(q, J=7.7 Hz, 1H), 7.35(m,1H), 7.13 (d, J=7.6 Hz,2H), 6.61 (d, J=8.9 Hz, 2H), 6.34 (d, J=8.9 Hz, 2H), 5.72(d, J=9.0 Hz,1H), 4.22(q, J=6.9 Hz, 1H), 3.56(s,3H), 1.55 (d, J=6.8 Hz,3H). Mass:408.27(M⁺+1).

Example 1662-(1-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of 6-chloro-7-deazapurine (0.100 g, 0.651 mmoles) in DMF(4 ml), cesium carbonate (0.424 g, 1.302 mmoles) was added and stirredat RT for 10 min. To this mixture intermediate 36 (0.452 g, 1.302mmoles) was added and stirred for 12 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.105 g, 38% yield). MP: 71-75° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ8.53(s,1H), 8.21(dd, J=7.9,1.4 Hz, 1H), 7.71(m,1H), 7.61 (d, J=3.7 Hz,1H), 7.44-7.36(m, 3H), 7.17-7.06(m, 3H), 6.69 (d, J=3.7 Hz, 1H), 6.14(q,J=7.2 Hz,1H), 1.90 (d, J=7.2 Hz, 3H). Mass: 420.10 (M+).

Example 1672-(1-(4-Chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of 4-chloro-1H-pyrazolo[3,4-b]pyridine (0.100 g, 0.711mmoles) in DMF (3 ml), cesium carbonate (0.463 g, 1.422 mmoles) wasadded and stirred at RT for 10 min. To this mixture intermediate 36(0.495 g, 1.422 mmoles) was added and stirred for 12 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as pale yellow solid (0.080 g, 27% yield). MP: 173-176° C.¹H-NMR (δ ppm, CDCl₃ 400 MHz): δ 8.29 (d, J=5.0 Hz, 1H), 8.20 (dd,J=8.0,71.5 Hz, 1H), 8.11(s,1H), 7.68(m,1H), 7.47 (d, J=8.5 Hz,1H),7.41-7.32(m, 2H), 7.12 (d, J=5.0 Hz, 1H), 7.03-6.95(m,3H), 6.20(q, J=7.2Hz, 1H), 2.02 (d, J=7.2 Hz, 3H). Mass: 419.96(M⁺+1).

Example 1682-(1-(4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.100 g, 0.745mmoles) in DMF (3 ml), cesium carbonate (0.485 g, 1.49 mmoles) was addedand stirred at RT for 10 min. To this mixture intermediate 36 (0.517 g,1.49 mmoles) was added and stirred for 12 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated under reduced pressure.The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.040 g,13% yield). MP: 197-201° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ8.21(s,1H), 8.19(d, J=1.4 Hz, 1H), 7.96(s,1H), 7.66(m,1H), 7.50 (d,J=8.4 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.327 m, 1H), 7.03(m,2H),6.90(m,1H), 6.05(q, J=7.1 Hz,1H), 1.95 (d, J=7.1 Hz,3H). Mass:419.87(M⁺+1).

Example 1692-(1-(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.100 g, 0.653mmoles) in DMF (4 ml), cesium carbonate (0.425 g, 1.30 mmoles) was addedand stirred at RT for 10 min. To this mixture intermediate 36 (0.455 g,1.30 mmoles) was added and stirred for 12 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated under reduced pressure.The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as light yellow solid(0.080 g, 29% yield). MP: 166-168° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ8.66(s,1H), 8.24(dd, J=7.9,1.4 Hz, 1H), 7.86 (d, J=3.4 Hz, 1H),7.78(m,1H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.30(m,2H),7.09 (dt, J=8.5,2.0 Hz, 1H), 6.80 (d, J=3.4 Hz, 1H), 6.74(m,1H), 6.50(q,J=7.1 Hz, 1H), 1.99 (d, J=7.1 Hz, 3H). Mass: 419.89(M+).

Example 1702-(1-(4-amino-3-(1,3-dimethyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), intermediate 115 (0.309 g, 1.137mmoles) and sodium carbonate (0.241 g, 2.27 mmoles) were added and thesystem is degassed for 30 min Tetrakistriphenylphosphine Palladium(0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heatedto 80° C. After 12 h, the reaction mixture was celite filtered,concentrated and extracted with ethyl acetate. The organic layer wasdried over sodium sulphate and concentrated under reduced pressure. Thecrude product was purified by column chromatography withmethanol:dichloromethane to afford the title compound as off-white solid(0.071 g, 17% yield). MP: 270-272° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 8.08(s,1H), 8.04(d, J=6.8 Hz, 1H), 7.84(m,2H), 7.69(s,1H), 7.69(d,J=10.8 Hz, 1H), 7.53(t, J=7.5 Hz, 1H), 7.33(d, J=8.3 Hz, 2H),7.03-6.95(m, 3H), 6.06(q, J=7.1 Hz, 1H), 3.99(s,3H), 2.48(s,3H), 1.92(d,J=7.0 Hz, 3H). Mass: 546.24(M⁺+1).

Example 1712-(1-(4-amino-3-(2,3-dimethyl-2H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml),ethanol (2 ml) and water (2 ml), intermediate 116 (0.309 g, 1.137mmoles) and sodium carbonate (0.241 g, 2.27 mmoles) were added and thesystem is degassed for 30 min Tetrakistriphenylphosphine Palladium(0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heatedto 80° C. After 12 h, the reaction mixture was celite filtered,concentrated and extracted with ethyl acetate. The organic layer wasdried over sodium sulphate and concentrated under reduced pressure. Thecrude product was purified by column chromatography withmethanol:dichloromethane to afford the title compound as off-white solid(0.100 g, 24% yield). MP: 269-274° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 8.08(s,1H), 8.04(d, J=8.0,1.5 Hz, 1H), 7.86(m,2H), 7.68(d, J=4.2 Hz,2H), 7.53(t, J=8.8 Hz, 1H), 7.35(m,1H), 7.24(m,1H), 7.07-6.84(m,3H),6.06 (q, J=6.9 Hz, 1H), 4.07(s,3H), 2.64(s,3H), 1.92(d, J=7.1 Hz, 3H).Mass: 546.03(M⁺+1).

Example 1722-(1-(4-amino-3-(6-methoxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 6-methoxynaphthalen-2-ylboronic acid (0.209 mmol). Brown solid (44.2mg, 42%). MP: 285-287° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.26(s,1H),8.22(dd, J=7.9,1.5 Hz, 1H), 8.06(s,1H), 7.91(d, J=8.5 Hz, 1H), 7.84(d,J=7.9 Hz, 1H), 7.76(dd, J=8.4,1.7 Hz, 1H), 7.69(m,1H), 7.50(d, J=8.2 Hz,1H), 7.42(dt, J=8.0,0.9 Hz, 1H), 7.31(m,1H), 7.24(m,2H),7.06-6.95(m,3H), 6.16(q, J=7.1 Hz, 1H), 5.44(s,2H), 3.96(s,3H), 2.05(d,J=7.1 Hz, 3H). Mass: 558.3(M⁺+1).

Example 1732-(1-(4-amino-3-(benzo[b]thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby benzo[b]thiophen-3-ylboronic acid (0.209 mmol). Brown solid (22.4 mg,22%). MP: 226-229° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.28(s,1H),8.23(dd, J=7.9,1.4 Hz, 1H), 8.01(d, J=7.6 Hz, 1H), 7.99(d, J=9.1 Hz,1H), 7.74(s,1H), 7.70(m,1H), 7.48-7.37(m,6H), 7.11-6.99(m,2H), 6.19(q,J=7.1 Hz, 1H), 5.35(s,2H), 2.05 (d, J=7.1 Hz, 3H). Mass: 534.3(M⁺+1).

Example 1742-(1-(4-amino-3-(2,4-dimethoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 2,4-dimethoxypyrimidin-5-ylboronic acid (0.209 mmol). Brown solid(28.2 mg, 26%). MP: 286-290° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ8.25(s,1H), 8.22(dd, J=8.0,1.5 Hz, 1H), 8.05(s,1H), 7.87(d, J=8.5 Hz,1H), 7.83(d, J=8.9 Hz, 1H), 7.75-7.65(m,2H), 7.50(d, J=8.2 Hz, 1H),7.42(dt, J=8.1,1.0 Hz, 1H), 7.35(m,1H), 7.24(m, 1H), 7.05-6.75(m,4H),6.14(q, J=7.2 Hz, 1H), 5.46(s,2H), 4.21(q, J=6.9 Hz, 2H), 2.04(d, J=7.1Hz, 3H), 1.52(t, J+6.9 Hz, 3H). Mass: 572.3(M⁺+1).

Example 1752-(1-(4-amino-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 6-ethoxynaphthalen-2-ylboronic acid (0.209 mmol). Brown solid (28.2mg, 26%). MP: 286-290° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.25(s,1H),8.22(dd, J=8.0,1.5 Hz, 1H), 8.05(s,1H), 7.87(d, J=8.5 Hz, 1H), 7.83(d,J=8.9 Hz, 1H), 7.75-7.65(m,2H), 7.50(d, J=8.2 Hz, 1H), 7.42(dt,J=8.1,1.0 Hz, 1H), 7.35(m,1H), 7.24(m,1H), 7.05-6.75(m,4H), 6.14(q,J=7.2 Hz, 1H), 5.46(s,2H), 4.21(q, J=6.9 Hz, 2H), 2.04(d, J=7.1 Hz, 3H),1.52(t, J+6.9 Hz, 3H). Mass: 572.3(M⁺+1).

Example 1763-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-cyclopropylbenzamide

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3-(cyclopropylcarbamoyl) phenylboronic acid (0.209 mmol). Reddishbrown solid (47 mg, 44%). MP: 127-132° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): δ 8.26(s,1H), 8.21(dd, J=7.9,1.4 Hz, 1H), 8.05(s,1H), 7.84(d,J=7.9 Hz, 1H), 7.69-7.47(m,4H), 7.42(t, J=7.1 Hz, 1H), 7.32(m,1H),7.03-6.93(m,3H), 6.32(s,1H), 6.13(q, J=7.1 Hz, 1H), 5.37(s,2H),2.95(m,1H), 2.02(d, J=7.1 Hz, 3H), 0.89(m,2H), 0.66(m,2H). Mass:561.3(M⁺+1).

Example 1772-(1-(4-amino-3-(3-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3-(morpholine-4-carbonyl)phenylboronic acid (0.209 mmol). Brown solid(30 mg, 26%). MP: 104-106° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ8.25(s,1H), 8.22(dd, J=7.9,1.5 Hz, 1H), 7.77-7.32(m,9H), 7.01(m,2H),6.12 (q, J=7.2 Hz, 1H), 5.44(s,2H), 3.78-3.55(m,8H), 2.01(d, J=7.1 Hz,3H). Mass: 591.3(M⁺+1).

Example 1782-(1-(4-amino-3-(3-(difluoromethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 3-(difluoromethoxy)phenylboronic acid (0.209 mmol). Brown solid (56mg, 54%). MP: 176-179° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 8.26(s,1H),8.22(dd, J=8.0,1.4 Hz, 1H), 7.70(m,1H), 7.55-7.32(m,7H),7.05-6.93(m,3H), 6.12(q, J=7.2 Hz, 1H), 5.42(s,2H), 2.02(d, J=7.1 Hz,3H). Mass: 544.3(M⁺+1).

Example 1795-(4-amino-1-(1-(3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)furan-2-carbaldehyde

The compound was prepared as per the procedure provided above forExample 130 wherein the 3,5-dimethoxy phenyl boronic acid was replacedby 5-formylfuran-2-ylboronic acid (0.209 mmol). Yellow solid (25 mg,27%). MP: 215-217° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): δ 9.65(s,1H),8.24(s,1H), 8.21(dd, J=7.8 Hz, 1H), 7.69(m,1H), 7.45(m,3H), 7.32(m,1H),7.17(d, J=3.7 Hz, 1H), 7.04(m,3H), 6.10(q, J=7.2 Hz, 1H), 1.99(d, J=7.1Hz, 3H). Mass: 496.3(M⁺+1).

Biological Assay

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The pharmacologicalassays which can be been carried out with the compounds according to theinvention and/or their pharmaceutically acceptable salts is exemplifiedbelow.

Assay 1: Fluorescent Determination of PI3Kinase Kinase Enzyme Activity

Phosphoinositide 3 kinases (PI3K) belong to a class of lipid kinasesthat play a critical role in the regulation of several key cellularprocesses. The PI3K are capable of phosphorylating the 3-hydroxyposition of phosphoinositols thereby generating second messengersinvolved in downstream signalling events. The homogenous time resolvedfluorescence (HTRF) assay allows detection of 3,4,5-triphosphate (PIPS)formed as a result of phosphorylation of phosphotidylinositol4,5-biphosphate (PIP2) by PI3K isoforms such as α, β, γ or δ.

PI3K isoform activity for α, β, γ or δ was determined using a PI3K humanHTRF™ Assay Kit (Millipore, Billerica, Mass.) with modifications. Allincubations were carried out at room temperature. Briefly, 0.5 μl of 40×inhibitor (in 100% DMSO) or 100% DMSO were added to each well of a384-well black plate (Greiner Bio-One, Monroe, N.C.) containing 14.5 μl1× reaction buffer/PIP2 (10 mM MgCl₂, 5 mM DTT, 1.38 μM PIP2) mix withor without enzyme and incubated for 10 mM After the initial incubation,5 μl/well of 400 μM ATP was added and incubated for an additional 30minutes. Reaction was terminated by adding 5 μl/well stop solution(Millipore, Billerica, Mass.). Five microliters of detection mix(Millipore, Billerica, Mass.) were then added to each well and wasincubated for 6-18 h in the dark. HRTF ratio was measured on amicroplate reader (BMG Labtech., Germany) at an excitation wavelength of337 nm and emission wavelengths of 665 and 620 nm with an integrationtime of 400 μsec. Data were analyzed using Graphpad Prism (Graphpadsoftware; San Diego Calif.) for IC50 determination. Percent inhibitionwas calculated based on the values for the blank and enzyme controls.The results are provided below in Table 2 & 3.

Assay 2: Selectivity for PI3Kδ in Isoform Specific Cell-Based Assays

Specificity of test compounds towards PI3Kδ can be confirmed usingisoform-specific cell based assays as outlined below:

-   PI3Kα: NIH-3T3 cells were seeded at a concentration of 0.5×10⁶ cells    per well in a 6-well tissue culture plate and incubated overnight.    Complete medium was replaced with serum-free media the following day    and compounds at the desired concentrations are to be added. After    15 min, 20 ng/ml PDGF was added and incubated for an additional 10    min Cells were then lysed and AKT phosphorylation was determined by    Western Blotting. Intensity of pAKT bands were normalized based on    Actin and Data were analysed using Graphpad Prism (Graphpad    software; San Diego Calif.) and % inhibition due to the test    compound compared to the control was calculated accordingly.-   PI3Kβ: NIH-3T3 cells were seeded at a concentration of 0.5×10⁶ cells    per well in a 6-well tissue culture plate and incubated overnight.    Complete medium was replaced with serum-free media the following day    and compounds at the desired concentrations were added. After 15 min    5 nM LPA was added and incubated for an additional 5 min Cells were    lysed and AKT phosphorylation was determined by Western Blotting.    Intensity of pAKT bands were normalized based on Actin and Data were    analysed using Graphpad Prism (Graphpad software; San Diego Calif.)    and % inhibition due to the test compound compared to the control    was calculated accordingly.-   PI3Kγ: RAW cells were seeded at a concentration of 1×10⁶ cells per    well in a 6-well tissue culture plate and incubated overnight.    Complete medium was replaced with serum-free media the following day    and compounds at the desired concentrations were added. After 15    min, 50 ng/ml c5a was added and incubated for an additional 10 min.    Cells were lysed and AKT phosphorylation was determined by Western    Blotting. Intensity of pAKT bands were normalized based on Actin and    data were analysed using Graphpad Prism (Graphpad software; San    Diego Calif.) and % inhibition due to the test compound compared to    the control was calculated accordingly.-   PI3Kδ: Compound specificity towards PI3Kδ was determined in an    IgM-induced B cell proliferation assay. Briefly, T-cells were    rosetted from human whole blood using sheep RBC and B-cells were    separated on a Ficoll-Hypaque gradient. Purified B-cells were seeded    at a concentration of 0.1×10⁶ cells per well in a 96-well tissue    culture plate and incubated with desired concentrations of the test    compound for 30 min Cells were stimulated with 5 μg/ml purified goat    anti-human IgM. Growth was assessed using the    3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MIT)    dye reduction test at 0 h (prior to the addition of the test    compound) and 48 h after the addition of test compound. Absorbance    was read on a Fluostar Optima (BMG Labtech, Germany) at a wave    length of 450 nm. Data were analysed using Graphpad Prism (Graphpad    software; San Diego Calif.) and % inhibition due to the test    compound compared to the control was calculated accordingly.

Compounds of the present invention when tested at 1 μM did not show anysignificant inhibition of Pi3kα isoform.

TABLE 2 P110 δ/Pi3K δ Compound % inhibition (1 μM) IC 50 nM Example 1 +A Example 2a − — Example 3 + — Example 4a + — Example 5 − — Example 6 +— Example 7 + — Example 8 − — Example 9 + — Example 10 − — Example 11 +— Example 12 + — Example 13 + — Example 14 + — Example 15 + — Example16 + — Example 17a − — Example 18a + — Example 19 − — Example 20 + —Example 21 + — Example 22 + — Example 23 ++ A Example 24 + — Example25 + — Example 26 + — Example 27 + — Example 28 + — Example 29 + —Example 30 + — Example 31 ++ B Example 32 ++ A Example 33 + — Example 34++ — Example 35 + — Example 36 + — Example 37 + — Example 38 + — Example39 + — Example 40 ++ — Example 41 ++ — Example 42 ++ A Example 43 + —Example 44 ++ — Example 45 + — Example 46 + — Example 47 ++ A Example48 + — Example 49 + — Example 50 ++ — Example 51a ++ A Example 52 +Example 53 ++ A Example 54 + — Example 55 ++ A Example 56 + — Example 57++ A Example 58 + — Example 59 ++ B Example 60 ++ A Example 61 + —Example 62 + — Example 63 + — Example 64 + — Example 65 + — Example 66a++ A Example 67 + — Example 68 ++ A Example 69 ++ — Example 70 ++ —Example 71 + — Example 72 ++ A Example 73 ++ — Example 74 ++ A Example75 ++ — Example 76a ++ — Example 77 ++ — + is less than equal to 50%inhibition at 1 μM; ++ is less than equal to 100% inhibition but morethan equal to 50% at 1 μM; A represents an IC 50 value of less thanequal to 250 nM; B represents an IC 50 value of 250-500 nM; C representsan IC 50 value of greater than 500 nM.

TABLE 2 P110 δ/Pi3K δ Compound % inhibition* IC 50 nM Example 78 + —Example 79 ++ A Example 80 + — Example 81 + — Example 82 ++ — Example 83++ — Example 84 ++ A Example 85 ++ — Example 86a ++ — Example 87 ++Example 88a ++ A Example 89 + Example 90 + Example 91 + Example 92 ++Example 93 ++ Example 94 ++ Example 95a ++ A Example 96a ++ Example 97++ Example 98 ++ A Example 99 ++ A Example 100 ++ Example 101 + Example102a + Example 103 ++ A Example 104 ++ A Example 105 ++ A Example 106 +Example 107a + Example 108 ++ A Example 109 ++ Example 110 ++ Example111 ++ Example 112 + Example 113 ++ Example 114 ++ Example 115 ++ AExample 116 ++ — Example 117 ++ Example 118 + Example 119 + Example 120a++ Example 121a ++ Example 122 + Example 123 + Example 124 + Example125 + Example 126a + Example 127a + Example 128 − A Example 129 − CExample 130 + Example 131 + Example 132 + Example 133 + Example 134 +Example 135 + Example 136 + Example 137 + Example 138 − Example 139 +Example 140 + Example 141 ++ A Example 142 + Example 143 + Example 144++ A Example 145 + Example 146 ++ Example 147 + Example 148 ++ Example149 + Example 150 + Example 151 ++ A Example 152 + Example 153 + Example154 + Example 155 ++ Example 156 + Example 157 + Example 158 ++ AExample 159 + Example 160 + Example 161 + Example 162 ++ Example 163 +Example 164 + Example 165 + Example 166 + Example 167 + Example 168 +Example 169 + Example 170 ++ Example 171 + Example 172 + Example 173 ++Example 174 − Example 175 − Example 176 + Example 177 + Example 178 ++Example 179 ++ + is less than equal to 50% inhibition at 1 μM; ++ isless than equal to 100% inhibition but more than equal to 50% at 1 μM; Arepresents an IC 50 value of less than equal to 250 nM; B represents anIC 50 value of 250-500 nM; C represents an IC 50 value of greater than500 nM; *@ 0.3 uM.

TABLE 3 % inhibition (1 μM) Compound P110α P110β P110γ Example 1 + + −Example 2 − − − Example 3 − − − Example 4 − − − Example 5 − − − Example6 − − − Example 7 − − − Example 8 − − − Example 9 − − − Example 10 + + −Example 11 − − − Example 12 − − − Example 13 − − − Example 14 − − −Example 15 − − Example 16 − − − Example 17 − + − Example 18 − − −Example 19 − − − Example 20 − − − Example 21 − − − Example 22 − − −Example 23 + + − Example 24 − − − Example 25 − − − Example 26 − − −Example 27 − − − Example 28 − − − Example 29 − − − Example 30 − − −Example 31 − − − Example 32 + + + Example 33 − − − Example 34 − − −Example 35 − − − Example 36 − − − Example 37 − − − Example 38 − − −Example 39 − − − Example 40 − − − Example 41 − − − Example 42 + ++ +Example 43 − − − Example 44 − − − Example 45 − − − Example 46 − − −Example 47 + ++ ++ Example 48 − − − Example 49 − − − Example 50 − − −Example 51 + +++ + Example 52 − − − Example 53 + +++ + Example 54 − − −Example 55 + + +++ Example 56 − − − Example 57 + ++ − Example 58 − − −Example 59 − − − Example 60 − − − Example 61 − − − Example 62 − − −Example 63 − − − Example 64 − − − Example 65 − − − Example 66 − − −Example 67 − − − Example 68 + ++ + Example 69 − − − Example 70 − − −Example 71 − − − Example 72 − − − Example 73 − − − Example 74 − ++ ++Example 75 − − − Example 76 − − − Example 77 − − − Example 78 − − −Example 79 + ++ ++ Example 80 − − − Example 81 − − − Example 82 − − −Example 83 − − − Example 84 + + − Example 85 ++ ++ − Example 86 Example87 Example 88 Example 89 Example 90 Example 91 Example 92 Example 93Example 94 Example 95 Example 96 Example 97 Example 98 Example 99Example 100 Example 101 Example 102 Example 103 Example 104 Example 105− +++ +++ Example 106 − + ++ Example 107 Example 108 − ++ +++ Example109 + + ++ Example 110 − + +++ Example 111 + + +++ Example 112 + + −Example 113 − + − Example 114 − + − Example 115 + + − Example 116 + + −Example 117 − + − Example 118 + ++ − Example 119 + + − Example 120 + + −Example 121 Example 122 − +++ − Example 123 − + − Example 124 + + −Example 125 + + − Example 126 − + − Example 127 − +++ − Example 128 + +++ Example 129 − ++ − Example 130 + + − Example 131 ++ + − Example 132Example 133 + +++ − Example 134 − ++ − Example 135 − ++ − Example 136 −++ − Example 137 − ++ − Example 138 − ++ − Example 139 − ++ ++ Example140 − ++ ++ Example 141 − ++ +++ Example 142 − ++ + Example 143 − ++ +Example 144 − +++ − Example 145 − ++ − Example 146 + − Example 147 ++ −Example 148 +++ − Example 149 ++ − Example 150 ++ Example 151 ++ Example152 + Example 153 + Example 154 + Example 155 + Example 156 ++ Example157 − Example 158 Example 159 Example 160 Example 161 Example 162Example 163 Example 164 Example 165 Example 166 Example 167 Example 168Example 169 Example 170 Example 171 Example 172 Example 173 Example 174Example 175 Example 176 Example 177 Example 178 Example 179 + is lessthan equal to 25% inhibition at 1 μM; ++ is less than equal to 50%inhibition but more than equal to 25% at 1 μM; +++ is less than equal to100% inhibition but more than equal to 50% at 1 μM;

Assay 3: In Vitro Cell Proliferation Assay in Leukemic Cell Lines

Growth inhibition assays were carried out using 10% FBS supplementedmedia. Cells were seeded at a concentration of 5000-20,000 cells/well ina 96-well plate. Test compound at a concentration range from 0.01 to10000 nM were added after 24 h. Growth was assessed using the3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dyereduction test at 0 h (prior to the addition of the test compound) and48 h after the addition of test compound. Absorbance was read on aFluostar Optima (BMG Labtech, Germany) at a wave length of 450 nm Datawere analysed using GraphPad Prism and % inhibition due to the testcompound compared to the control was calculated accordingly. Exemplarycompounds of the present invention when tested @ 1 uM in THP-1; DLBCL;HL-60; MDA-MB-468; RPMI8226 and TOLEDO cell lines showed a 20 to 80%inhibition.

Assay 4: Determination of Cytotoxicity in Leukemic Cell Lines

Cytotoxicity of test compounds was determined using a lactatedehydrogenase assay kit (Cayman Chemicals, MI) as per the manufacturer'sinstructions with some minor modifications. Briefly, 20,000 cells/wellin complete RPMI-1640 media were seeded in a 96-well tissue cultureplate and incubated overnight at 37° C. and 5% CO₂. Inhibitors wereadded to the wells in triplicate at the desired concentrations.Doxorubicin and/or 1% Triton-X were used as a positive control. After 48h, media was removed and assayed for lactate dehydrogenase in acolorimetric assay. Optical density was measured on a microplate reader(BMG Labtech., Germany) at 490 nM. Data were analyzed using GraphpadPrism (Graphpad software; San Diego Calif.).

Results: Exemplary compounds of the present invention were found to benon-toxic when tested @ 10 uM.

Assay 5: Inhibition of PI3Kδ Signalling in Basophils from Human WholeBlood

PI3Kδ signalling in basophils manifested by an alteration of anti-FcεRIinduced CD63 expression is a useful pharmacodynamic marker determinedusing the Flow2CAST® kit (Buhlmann Laboratories, Switzerland). Briefly,it involves the following steps:

-   -   Mix the anti-coagulated blood sample by inverting the        venipuncture tube several times    -   Prepare fresh and pyrogen-free 3.5 ml polypropylene or        polystyrene tubes suitable for Flow Cytometry measurements    -   Add 49 μl of patient's whole blood to each tube.    -   Add 1 μl of 10% DMSO (background) or compound (10% DMSO) to the        assigned tubes and mix gently. Incubate at room temperature for        15 min    -   Pipet 50 μl of the Stimulation buffer (background) or anti-FcεRI        Ab to each tube    -   Add 100 μl of Stimulation Buffer to each tube    -   Mix gently. Add 20 μl Staining Reagent (1:1 mix of FITC-CD63 and        PE-CCR3) to each tube    -   Mix gently, cover the tubes and incubate for 15 minutes at        37° C. in a water bath. (using an incubator will take about 10        minutes longer incubation time due to less efficient heat        transfer)    -   Add 2 ml pre-warmed (18-28° C.) Lysing Reagent to each tube, mix        gently    -   Incubate for 5-10 minutes at 18-28° C.    -   Centrifuge the tubes for 5 minutes at 500×g    -   Decant the supernatant by using blotting paper    -   Resuspend the cell pellet with 300-800 μl of Wash Buffer    -   Vortex gently and acquire the data on the flow cytometer within        the same day.    -   Percent CD63 positive cells within the gated basophil population        are to be determined in different treatment groups and        normalized to vehicle control.

Assay 6: Inhibition of Apoptosis in Leukemic Cell Lines

Apoptosis in leukemic cells was determined using an in-situ Caspase 3kit (Millipore, US) as outlined below:

-   -   Seed leukemic cells—at a density of 1×10⁶ cells/well in a 6 well        plate    -   Add test compound/DMSO at desired concentrations    -   Incubate the plate for 24 hrs at 37° C. in 5% CO₂ incubator    -   Collect cells in a 2 ml centrifuge tube    -   Add 1.6 μL of freshly prepared 5×FLICA reagent and mix cells by        slightly flicking the tubes    -   Incubate tubes for 1 hour at 37° C. under 5% CO₂    -   Add 2 ml of 1× wash buffer to each tube and mix    -   Centrifuge cells at <400×g for 5 minutes at room temperature.    -   Carefully remove and discard supernatant, and gently vortex cell        pellet to disrupt any cell-to-cell clumping.    -   Resuspend cell pellet in 300 ul of 1× wash buffer    -   Place 100 μL of each cell suspension into each of two wells of a        black microtiter plate. Avoid creation of bubbles.    -   Read absorbance of each microwell using an excitation wavelength        of 490 nm and an emission wavelength of 520 nm    -   Percent increase in caspase-3 activity manifested by an increase        in fluorescence compared to the control blank is to be        calculated.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as described above. It is intended that theappended claims define the scope of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

All publications and patent and/or patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication or patent application was specificallyand individually indicated to be incorporated herein by reference.

We claim:
 1. A method for the treatment of chronic lymphocytic leukemia(CLL), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML),multiple myeloma (MM), or small lymphocytic lymphoma (SLL), comprisingthe step of administering to a subject in need thereof an effectiveamount of compound of the formula

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein each occurrence of R is independently selected fromhydrogen, halogen, —OR^(f) (wherein R^(f) is substituted orunsubstituted (C₁₋₆)alkyl), CN, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₈ cycloalkyl, andsubstituted or unsubstituted heterocyclic group; R¹ and R² may be thesame or different and are independently selected from hydrogen, halogen,and substituted or unsubstituted C₁₋₆ alkyl, or both R¹ and R² directlybound to a common atom, may be joined to form a substituted orunsubstituted saturated or unsaturated 3-10 member ring (including thecarbon atom to which R¹ and R² are bound), which may optionally includeone or more heteroatoms which may be the same or different and areselected from O, NR^(a) and S; Cy¹ is a monocyclic group selected fromsubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclic group, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; Cy² is selected from a substituted orunsubstituted heterocyclic group, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl; L₁ is selected from —S(═O)_(q)—and —NR^(a)—; each occurrence of R^(a) is selected from hydrogen,halogen, hydroxy, cyano, substituted or unsubstituted (C₁₋₆)alkyl,—NR^(c)R^(d) (wherein R^(c) and R^(d) are independently hydrogen,halogen, hydroxy, cyano, substituted or unsubstituted (C₁₋₆)alkyl, and(C₁₋₆)alkoxy) and —OR^(c) (wherein R^(c) is substituted or unsubstituted(C₁₋₆)alkyl); n is an integer from 1 to 4; and q is 0, 1 or
 2. 2. Themethod of claim 1, where the compound of formula (I) is selected fromthe group consisting of:2-((9H-Purin-6-ylthio)methyl)-3-phenyl-4H-chromen-4 -one;2-[(9H-Purin-6-ylthio)methyl]-6-bromo-3-phenyl-4H-chromen-4-one;2-(1-(9H-Purin-6-ylthio)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;(S)-2-(1 -(9H-purin-6-ylamino)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-6-bromo-3-phenyl-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-3-phenyl-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-3-(2-fluorophenyl)-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;(R)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one;(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenyl-4H-chromen-4-one;(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;2-((9H-purin-6-ylamino)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one;(R)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;6-Fluoro-3-(3-fluorophenyl)-2-(1-(4-methoxyphenylamino)ethyl)-4H-chromen-4-one,and pharmaceutically acceptable salts thereof.
 3. A method for thetreatment of a chronic lymphocytic leukemia (CLL), non-Hodgkin'slymphoma (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), orsmall lymphocytic lymphoma (SLL), comprising the step of administeringto a subject in need thereof an effective amount of compound of theformula

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptableester thereof, prodrug thereof, or pharmaceutically acceptable saltthereof, wherein each occurrence of R is independently selected fromhydrogen, halogen, —OR^(f) (wherein R^(f) is substituted orunsubstituted (C₁₋₆)alkyl), substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₈ cycloalkyl, andsubstituted or unsubstituted heterocyclic group; R¹ and R² may be thesame or different and are independently selected from hydrogen, halogen,and substituted or unsubstituted C₁₋₆ alkyl, or both R¹ and R² directlybound to a common atom, may be joined to form a substituted orunsubstituted saturated or unsaturated 3-10 member ring (including thecarbon atom to which R¹ and R² are bound), which may optionally includeone or more heteroatoms which may be the same or different and areselected from O, NR^(a) and S; Cy^(l) is a monocyclic group selectedfrom substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclic group, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl; Cy² is selected from asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl; L₁ isselected from —S(═O)_(q)— and —NR^(a)—; each occurrence of R^(a) isselected from hydrogen, halogen, hydroxy, cyano, and substituted orunsubstituted (C₁₋₆)alkyl; n is an integer from 1 to 4; and q is 0, 1 or2.
 4. The method of claim 1, wherein the non-Hodgkin's lymphoma isindolent non-Hodgkin's lymphoma (I-NHL).
 5. The method of claim 3,wherein the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma(I-NHL).